ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (incidence >= percent) with estradiol and norethindrone acetate tablets 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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)] o Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] o 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 estradiol and norethindrone acetate tablets mg/0.5 mg by investigators during clinical trials 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 Estradiol and Norethindrone Acetate Tablets mg/0.5 mg Endometrial Hyperplasia Study(12-Months)Vasomotor Symptoms Study(3-Months)Osteoporosis Study(2-Years)Estradiol and Norethindrone Acetate Tablets1 mg/0.5 mg(n=295)1 mg E2(n=296)Estradiol and Norethindrone Acetate Tablets1 mg/0.5 mg(n=29)Placebo(n=34)Estradiol and Norethindrone Acetate Tablets1 mg/0.5 mg(n=47)Placebo(n=48)Body as Whole Back Pain 6% 5% 3% 3% 6% 4% Headache 16% 16% 17% 18% 11% 6% Digestive System Nausea 3% 5% 10% 0% 11% 0% Gastroenteritis 2% 2% 0% 0% 6% 4% Nervous System Insomnia 6% 4% 3% 3% 0% 8% Emotional Lability 1% 1% 0% 0% 6% 0% Respiratory System Upper Respiratory Tract Infection 18% 15% 10% 6% 15% 19% Sinusitis 7% 11% 7% 0% 15% 10% Metabolic and Nutritional Weight Increase 0% 0% 0% 0% 9% 6% Urogenital System Breast Pain 24% 10% 21% 0% 17% 8% Post-Menopausal Bleeding 5% 15% 10% 3% 11% 0% Uterine Fibroid 5% 4% 0% 0% 4% 8% Ovarian Cyst 3% 2% 7% 0% 0% 8% Resistance Mechanism Infection Viral 4% 6% 0% 3% 6% 6% Moniliasis Genital 4% 7% 0% 0% 6% 0% Secondary Terms Injury Accidental 4% 3% 3% 0% 17%including one upper extremity fracture in each group 4% Other Events 2% 3% 3% 0% 6% 4% Adverse reactions reported with estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg by investigators during clinical trials 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 Estradiol and Norethindrone Acetate Tablets 0.5 mg/0.1 mg Estradiol and Norethindrone Acetate Tablets 0.5 mg/0.1 mg (n=194)Placebo(n=200)Body as Whole Back Pain 10% 4% Headache 22% 19% Pain in extremity 5% 4% Digestive System Nausea 5% 4% Diarrhea 6% 6% Respiratory System Nasopharyngitis 21% 18% Urogenital System Endometrial thickening 10% 4% Vaginal hemorrhage 26% 12% 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of estradiol and norethindrone acetate tablets. 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 System Changes 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. Breast Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction, stroke; increase in blood pressure. Gastrointestinal Nausea, vomiting; changes in appetite; cholestatic jaundice; abdominal pain/cramps, flatulence, bloating; increased incidence of gallbladder disease and pancreatitis. Skin Chloasma 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. Eyes Retinal vascular thrombosis, intolerance to contact lenses. Central Nervous System Headache; migraine; dizziness; mental depression; chorea; insomnia; nervousness; mood disturbances; irritability; exacerbation of epilepsy; dementia. Miscellaneous Increase 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, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER. WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCERSee full prescribing information for complete boxed warning Estrogen Plus Progestin Therapy oThe 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)oThe WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2)oThe 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)oDo not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia (5.1, 5.3)Estrogen-Alone Therapy oThere is an increased risk of endometrial cancer in woman with uterus who use unopposed estrogens (5.2) oThe WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1) oThe 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)oDo not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia (5.2, 5.3) oThe 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). oThe WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2). oThe 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). oDo not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia (5.1, 5.3). oThere is an increased risk of endometrial cancer in woman with uterus who use unopposed estrogens (5.2) oThe WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1) oThe 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). oDo not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia (5.2, 5.3) Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable DementiaThe 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 and 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)]. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 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)]. Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.Estrogen-Alone Therapy Endometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestogen 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 DementiaThe 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 and 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)]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

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. Generally, serum estrogen concentration does not predict an individual womans therapeutic response to estradiol and norethindrone acetate tablets nor her risk for adverse outcomes. Likewise, exposure comparisions across different estrogen products to infer efficacy or safety for the individual woman may not be valid.. 12.3 Pharmacokinetics. AbsorptionEstradiol Estradiol is absorbed through the gastrointestinal tract. Following oral administration of estradiol and norethindrone acetate tablets, peak plasma estradiol concentrations are reached within to hours. The oral bioavailability of estradiol following administration of estradiol and norethindrone acetate tablets mg/0.5 mg when compared to combination oral solution is 53%. Administration of estradiol and norethindrone acetate tablets 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 estradiol and norethindrone acetate tablets. The oral bioavailability of norethindrone following administration of estradiol and norethindrone acetate tablets mg/0.5 mg when compared to combination oral solution is 100%. Administration of estradiol and norethindrone acetate tablets mg/0.5 mg with food increases norethindrone AUC0-72 by 19% and decreases Cmax by 36%. The pharmacokinetic parameters of estradiol (E2), estrone (E1), and norethindrone (NET) following oral administration of estradiol and norethindrone acetate tablet mg/0.5 mg or estradiol and norethindrone acetate tablets 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 Estradiol and Norethindrone Acetate mg/0.5 mg or Tablets of Estradiol and Norethindrone Acetate 0.5 mg/0.1 mg to Healthy Postmenopausal Women x Estradiol and Norethindrone Acetate Tablets2 Estradiol and Norethindrone Acetate Tablets1 mg/0.5 mg0.5 mg/0.1 mg(n=24)(n=24)Meangeometric mean; (%CV)geometric coefficient of variation;Mean (%CV)Estradiolbaseline unadjusted data; (E2) AUC0-t (pg/mLh) 766.5 (48) 697.3 (53) Cmax (pg/mL) 26.8 (36) 26.5 (37) tmax (h): median (range) 6.0 (0.5-16.0) 6.5 (0.5-16.0) t1/2 (h)baseline unadjusted data 14.0n=18; (29) 14.5n=16; (27) Estrone (E1) AUC0-t (pg/mLh) 4469.1 (48) 4506.4 (44) Cmax (pg/mL) 195.5 (37) 199.5 (30) tmax (h): median (range) 6.0 (1.0-9.0) 6.0 (2.0-9.0) t1/2 (h) 10.7 (44)n=13; 11.8 (25) Norethindrone (NET) AUC0-t (pg/mLh) 21043 (41) 8407.2 (43) Cmax (pg/mL) 5249.5 (47) 2375.4 (41) tmax (h) median (range) 0.7 (0.7-1.25) 0.8 (0.7-1.3) t1/2 (h) 9.8 (32)n=22; 11.4 (36)n=21 AUC area under the curve, - last quantifiable sampleCmax maximum plasma concentration,tmax time at maximum plasma concentration,t1/2 half-life,Following continuous dosing with once-daily administration of estradiol and norethindrone acetate tablets 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 estradiol and norethindrone acetate tablets 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 Estradiol and Norethindrone Acetate Tablets mg/0.5 mg (N=24)Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of Estradiol and Norethindrone Acetate Tablets mg/0.5 mg (N=24)DistributionEstradiolThe 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%). MetabolismEstradiolExogenous 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 estradiol and norethindrone acetate tablets mg/0.5 mg is 12 to 14 hours.Norethindrone Acetate The terminal half-life of norethindrone is about to 11 hours. Figure 1a. Figure 1b.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women. In 12-week randomized clinical trial involving 92 subjects, estradiol and norethindrone acetate tablets mg/0.5 mg were 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 estradiol and norethindrone acetate tablets mg/0.5 mg and the mg estradiol group compared to placebo (see Figure 2). Figure 2: Mean Weekly Number of Moderate and Severe Hot Flushes in 12-Week Study In study conducted in Europe total of 577 postmenopausal women were randomly assigned to either estradiol and norethindrone acetate tablets 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 estradiol and norethindrone acetate tablets 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 Through 12 Figure 2. Figure 03. 14.2 Effects on the Endometrium in Postmenopausal Women. Estradiol and norethindrone acetate tablets mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at year in randomized, controlled clinical trial. This trial enrolled 1,176 postmenopausal women 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 estradiol and norethindrone acetate tablets mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 women. The results of the mg estradiol unopposed arm compared to estradiol and norethindrone acetate tablets mg/0.5 mg are shown in Table 4. Table 4: Incidence of Endometrial Hyperplasia with Unopposed Estradiol and Estradiol and Norethindrone Acetate Tablets mg/0.5 mg in 12-Month StudyEstradiol and Norethindrone Acetate Tablets1 mg E2 mg E2/0.5 mg NETA1 mg E2/0.25 mg NETA1 mg E2/0.1 mg NETA(n=296)(n=295)(n=291)(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 in Postmenopausal Women. During the initial months of therapy, irregular bleeding or spotting occurred with estradiol and norethindrone acetate tablets mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with estradiol and norethindrone acetate tablets mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4). Figure 4: Patients Treated with Estradiol and Norethindrone Acetate Tablets 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 estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after months of treatment (See Figure 5). Figure 5: Patients Treated with Estradiol and Norethindrone Acetate Tablets 0.5 mg/0.1 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent to Treat Population, LOCF Figure 4. Figure 5. 14.4 Effects on Bone Mineral Density in Postmenopausal Women. The results of two randomized, multicenter, calcium-supplemented (500 to 1,000 mg per day), placebo-controlled, year clinical trials have shown that estradiol and norethindrone acetate tablets 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 -2.0) 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). summary of the results comparing estradiol and norethindrone acetate tablets 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 Estradiol and Norethindrone Acetate Tablets mg/0.5 mg and 0.5 mg E2 While estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD; therefore the BMD changes expected from treatment with estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. (Intent to Treat Analysis, Last Observation Carried Forward)US TrialEU TrialPlacebo 0.5 mg E2 Estradiol and Norethindrone Acetate Tablets 1mg/0.5 mgPlacebo Estradiol and Norethindrone Acetate Tablets mg/0.5 mg(n=37)(n=31)(n=37)(n=40)(n=38)Lumbar spine -2.1 +- 2.9 2.3 +- 2.8 Significantly (p<0.001) different from placebo 3.8 +- 3.0 -0.9 +- 4.0 5.4 +- 4.8 Femoral neck -2.3 +- 3.4 0.3 +- 2.9 Significantly (p<0.007) different from placebo 1.8 +- 4.1 -1.0 +- 4.6 0.7 +- 6.1 Femoral trochanter -2.0 +- 4.3 1.7 +- 4.1 Significantly (p<0.002) different from placebo 3.7 +- 4.3 0.8 +- 6.9 6.3 +- 7.6 US= United States, EU European The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between estradiol and norethindrone acetate tablets 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. Estradiol and norethindrone acetate tablets mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials for estradiol and norethindrone acetate tablets 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 Estradiol and Norethindrone Acetate Tablets mg/0.5 mg and Estradiol 0.5 mg (Intent to Treat Analysis with Last Observation Carried Forward) Figure 06. 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 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 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. EventRelative RiskCE/MPA versus Placebo(95 percent nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CE/MPAn 8,506Placebon 8,102Absolute Risk per 10,000 Women-YearsCHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63)3125 CHD death 1.10 (0.70-1.75)88All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90)2618Deep vein thrombosisNot included in global index. 1.95 (1.43-2.67) 2613Pulmonary embolism 2.13 (1.45-3.11) 18 Invasive breast cancerIncludes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer. 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer 0.81 (0.48-1.36) 7 Cervical cancer 1.44 (0.47-4.42) 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 All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19) 52 52 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. 1.13 (1.02-1.25) 184 165 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 non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].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 WHIAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. EventRelative RiskCE versus Placebo(95 percent 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 fractures.9The 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, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].. 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise women to read the FDA-approved patient labeling (Patient Information) Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)]. Possible Serious Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3)]. Possible Common Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestogen therapy such as headache, breast pain and tenderness, nausea and vomiting.Rx OnlyPatient InformationEstradiol and Norethindrone Acetate Tablets USP, for oral useRead this Patient Information before you start using estradiol and norethindrone acetate tablets 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.. Vaginal Bleeding Possible Serious Adverse Reactions with Estrogen Plus Progestogen Therapy . What is the most important information should know about estradiol and norethindrone acetate tablets (a combination of estrogen and progestogen) oDo not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function).oUsing estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. oUsing estrogens with progestogens may increase your chance of getting dementia, based on study of women 65 years of age and older. oUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb). oDo not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). oUsing estrogen-alone may increase your chances of getting strokes or blood clots. oUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age and older. oOnly one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of estradiol and norethindrone acetate tablets will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol and norethindrone acetate tablets.. oDo not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function).. oUsing estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. oUsing estrogens with progestogens may increase your chance of getting dementia, based on study of women 65 years of age and older. oUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb). oDo not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). oUsing estrogen-alone may increase your chances of getting strokes or blood clots. oUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age and older. oOnly one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of estradiol and norethindrone acetate tablets will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol and norethindrone acetate tablets.. What are estradiol and norethindrone acetate tablets Estradiol and norethindrone acetate tablets are prescription medicine that contains two kinds of hormones, an estrogen and progestogen. What are estradiol and norethindrone acetate tablets used for Estradiol and norethindrone acetate tablets are used after menopause to: oReduce moderate to severe hot flushes Estrogens are hormones made by womans ovaries. The ovaries normally stop making estrogens when woman is between 45 and 55 yrs old. This drop in body estrogen levels causes the change of life or menopause, the end of monthly menstrual periods. Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes surgical menopause. When estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden, intense feelings of heat and sweating (hot flashes or hot flushes). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe. oTreat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with estradiol and norethindrone acetate tablets mg/0.5 mg to treat these problems. If you use estradiol and norethindrone acetate tablets mg/0.5 mg only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether topical vaginal product would be better for you. oHelp reduce your chances of getting osteoporosis (thin weak bones) Osteoporosis from menopause is thinning of the bones that makes them weaker and easier to break. If you use estradiol and norethindrone acetate tablets to prevent osteoporosis due to menopause, talk with your healthcare provider about whether different treatment or medicine without estrogens might be better for you.You and your healthcare provider should talk regularly about whether you still need treatment with estradiol and norethindrone acetate tablets. Who should not use estradiol and norethindrone acetate tablets Do not use estradiol and norethindrone acetate tablets if you have had your uterus (womb) removed (hysterectomy). Estradiol and norethindrone acetate tablets contain progestogen to decrease the chance of getting cancer of the uterus. If you do not have uterus, you do not need progestogen and you should not use estradiol and norethindrone acetate tablets.Do not start using estradiol and norethindrone acetate tablets if you: ohave unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. ohave been diagnosed with bleeding disorderocurrently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol and norethindrone acetate tablets. ohad stroke or heart attack ocurrently have or have had blood clots ocurrently have or have had liver problems oare allergic to estradiol and norethindrone acetate tablets or any of the ingredients in it.See the list of ingredients in estradiol and norethindrone acetate tablets at the end of this leaflet. Before you use estradiol and norethindrone acetate tablets, tell your healthcare provider about all of your medical conditions, including if you:ohave any unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have any other medical conditions that may become worse while you are using estradiol and norethindrone acetate tabletsohave any other medical conditions that may become worse while you are using estradiol and norethindrone acetate tablets Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. oare going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop using estradiol and norethindrone acetate tablets. oare pregnant or think you may be pregnant. Estradiol and norethindrone acetate tablets are not for pregnant women.oare breast feeding The hormones in estradiol and norethindrone acetate tablets can pass into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol and norethindrone acetate tablets work. Estradiol and norethindrone acetate tablets may also affect how your other medicines work. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should use estradiol and norethindrone acetate tablets oUse estradiol and norethindrone acetate tablets exactly as your healthcare provider tells you to use it.oTake tablet at the same time each day.oYou and your healthcare provider should talk regularly (every to months) about your dose and whether you still need treatment with estradiol and norethindrone acetate tablets.Follow the instructions below to use your estradiol and norethindrone acetate tablets blister pack. 1. Set the Day ReminderoEach blister pack is printed with days of the week, starting with SUN (Sunday) to facilitate Sunday-Start regimen.oSix different day label strips of the week have been provided with this pack in order to accommodate beginning any day of the week.oPick the day label strip that starts with the current day of the week. Place this day label strip over the area that has the days of the week (starting with Sunday) pre-printed on the blister pack (Refer figure below).2. How to Take the First TabletRemove the tablet by pushing it through the blister. The tablet will come out through the blister pack.3. Every DayoThe patient should wait 24 hours to take the next tablet. Moving across each row of the blister pack, continue taking tablet daily until all tablets have been taken.oWhen your blister pack is empty, you will start new blister pack on the day after tablet 28. The first tablet in every refill will always be taken on the same day of the week.What are the possible side effects of estradiol and norethindrone acetate tabletsSide effects are grouped by how serious they are and how often they happen when you are treated.Serious, but less common side effects include:oheart attackostrokeoblood clotsobreast cancerocancer of the lining of the uterus (womb)ocancer of the ovaryodementiaohigh or low blood calcium levels ogallbladder diseaseovisual abnormalities ohigh blood pressureohigh levels of fat (triglycerides) in your blood oliver problemsochanges in your thyroid hormone levelsofluid retentionocancer changes of endometriosisoenlargement of benign tumors of the uterus (fibroids)oworsening swelling of face and tongue (angioedema) in women who have history of angioedemaochanges in laboratory tests results such as bleeding times and high blood sugar levelsCall your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:onew breast lumpsounusual vaginal bleedingochanges in vision or speechosudden new severe headachesosevere pains in your chest or legs with or without shortness of breath, weakness and fatigue Common side effects of estradiol and norethindrone acetate tablets include:oirregular vaginal bleeding or spotting onausea ostomach or abdominal cramps, bloating oheadacheovomitingoback pain obreast painodiarrhea ofluid retention ovaginal yeast infection These are not all the possible side effects of estradiol and norethindrone acetate tablets. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away. You may report side effects to Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or to FDA at 1-800-FDA-1088. What can do to lower my chances of serious side effect with estradiol and norethindrone acetate tablets oTalk with your healthcare provider regularly about whether you should continue using estradiol and norethindrone acetate tablets. oIf you have uterus, talk with your healthcare provider about whether estradiol and norethindrone acetate tablets are right for you.oIn general, the addition of progestogen is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus (womb). oSee your healthcare provider right away if you get vaginal bleeding while using estradiol and norethindrone acetate tablets. oHave pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. oIf members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have breast exams more often. oIf you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. oAsk your healthcare provider for ways to lower your chances for getting heart disease. How should store estradiol and norethindrone acetate tablets oStore estradiol and norethindrone acetate tablets at room temperature between 20 to 25C (68 to 77F).oStore estradiol and norethindrone acetate tablets in dry place protected from light.Keep estradiol and norethindrone acetate tablets and all medicines out of the reach of children. General information about the safe and effective use of estradiol and norethindrone acetate tablets. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use estradiol and norethindrone acetate tablets for conditions for which they were not prescribed. Do not give estradiol and norethindrone acetate tablets to other people, even if they have the same symptoms you have. They may harm them. You can ask your healthcare provider or pharmacist for information about estradiol and norethindrone acetate tablets that is written for health professionals. For more information call 1-877-446-3679 (1-877-4-INFO-RX). What are the ingredients in estradiol and norethindrone acetate tabletsActive ingredients: estradiol and norethindrone acetateInactive Ingredients: maize starch, lactose monohydrate, FD&C Yellow No. 6, copovidone, talc and magnesium stearate. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for:Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Manufactured by:Mylan Laboratories LimitedAhmedabad 382 213, IndiaCode No.: GUJ-DRUGS/G/28/129775082577Revised: 10/2021FC:OT:7294/7295:R6. oReduce moderate to severe hot flushes oTreat moderate to severe menopausal changes in and around the vagina oHelp reduce your chances of getting osteoporosis (thin weak bones) ohave unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. ohave been diagnosed with bleeding disorder. ocurrently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol and norethindrone acetate tablets. ohad stroke or heart attack ocurrently have or have had blood clots ocurrently have or have had liver problems oare allergic to estradiol and norethindrone acetate tablets or any of the ingredients in it.See the list of ingredients in estradiol and norethindrone acetate tablets at the end of this leaflet. ohave any unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have any other medical conditions that may become worse while you are using estradiol and norethindrone acetate tablets. ohave any other medical conditions that may become worse while you are using estradiol and norethindrone acetate tablets. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. oare going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop using estradiol and norethindrone acetate tablets. oare pregnant or think you may be pregnant.. Estradiol and norethindrone acetate tablets are not for pregnant women.. oare breast feeding The hormones in estradiol and norethindrone acetate tablets can pass into your breast milk. oUse estradiol and norethindrone acetate tablets exactly as your healthcare provider tells you to use it.. oTake tablet at the same time each day.. oYou and your healthcare provider should talk regularly (every to months) about your dose and whether you still need treatment with estradiol and norethindrone acetate tablets.. oEach blister pack is printed with days of the week, starting with SUN (Sunday) to facilitate Sunday-Start regimen.. oSix different day label strips of the week have been provided with this pack in order to accommodate beginning any day of the week.. oPick the day label strip that starts with the current day of the week. Place this day label strip over the area that has the days of the week (starting with Sunday) pre-printed on the blister pack (Refer figure below).. oThe patient should wait 24 hours to take the next tablet. Moving across each row of the blister pack, continue taking tablet daily until all tablets have been taken.. oWhen your blister pack is empty, you will start new blister pack on the day after tablet 28. The first tablet in every refill will always be taken on the same day of the week.. oheart attack. ostroke. oblood clots. obreast cancer. ocancer of the lining of the uterus (womb). ocancer of the ovary. odementia. ohigh or low blood calcium levels ogallbladder disease. ovisual abnormalities ohigh blood pressure. ohigh levels of fat (triglycerides) in your blood oliver problems. ochanges in your thyroid hormone levels. ofluid retention. ocancer changes of endometriosis. oenlargement of benign tumors of the uterus (fibroids). oworsening swelling of face and tongue (angioedema) in women who have history of angioedema. ochanges in laboratory tests results such as bleeding times and high blood sugar levels. onew breast lumps. ounusual vaginal bleeding. ochanges in vision or speech. osudden new severe headaches. osevere pains in your chest or legs with or without shortness of breath, weakness and fatigue oirregular vaginal bleeding or spotting onausea ostomach or abdominal cramps, bloating oheadache. ovomiting. oback pain obreast pain. odiarrhea ofluid retention ovaginal yeast infection oTalk with your healthcare provider regularly about whether you should continue using estradiol and norethindrone acetate tablets. oIf you have uterus, talk with your healthcare provider about whether estradiol and norethindrone acetate tablets are right for you.. oIn general, the addition of progestogen is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus (womb). oSee your healthcare provider right away if you get vaginal bleeding while using estradiol and norethindrone acetate tablets. oHave pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. oIf members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have breast exams more often. oIf you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. oAsk your healthcare provider for ways to lower your chances for getting heart disease. oStore estradiol and norethindrone acetate tablets at room temperature between 20 to 25C (68 to 77F).. oStore estradiol and norethindrone acetate tablets in dry place protected from light.. Blister 1-0.5.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionEstradiol Estradiol is absorbed through the gastrointestinal tract. Following oral administration of estradiol and norethindrone acetate tablets, peak plasma estradiol concentrations are reached within to hours. The oral bioavailability of estradiol following administration of estradiol and norethindrone acetate tablets mg/0.5 mg when compared to combination oral solution is 53%. Administration of estradiol and norethindrone acetate tablets 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 estradiol and norethindrone acetate tablets. The oral bioavailability of norethindrone following administration of estradiol and norethindrone acetate tablets mg/0.5 mg when compared to combination oral solution is 100%. Administration of estradiol and norethindrone acetate tablets mg/0.5 mg with food increases norethindrone AUC0-72 by 19% and decreases Cmax by 36%. The pharmacokinetic parameters of estradiol (E2), estrone (E1), and norethindrone (NET) following oral administration of estradiol and norethindrone acetate tablet mg/0.5 mg or estradiol and norethindrone acetate tablets 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 Estradiol and Norethindrone Acetate mg/0.5 mg or Tablets of Estradiol and Norethindrone Acetate 0.5 mg/0.1 mg to Healthy Postmenopausal Women x Estradiol and Norethindrone Acetate Tablets2 Estradiol and Norethindrone Acetate Tablets1 mg/0.5 mg0.5 mg/0.1 mg(n=24)(n=24)Meangeometric mean; (%CV)geometric coefficient of variation;Mean (%CV)Estradiolbaseline unadjusted data; (E2) AUC0-t (pg/mLh) 766.5 (48) 697.3 (53) Cmax (pg/mL) 26.8 (36) 26.5 (37) tmax (h): median (range) 6.0 (0.5-16.0) 6.5 (0.5-16.0) t1/2 (h)baseline unadjusted data 14.0n=18; (29) 14.5n=16; (27) Estrone (E1) AUC0-t (pg/mLh) 4469.1 (48) 4506.4 (44) Cmax (pg/mL) 195.5 (37) 199.5 (30) tmax (h): median (range) 6.0 (1.0-9.0) 6.0 (2.0-9.0) t1/2 (h) 10.7 (44)n=13; 11.8 (25) Norethindrone (NET) AUC0-t (pg/mLh) 21043 (41) 8407.2 (43) Cmax (pg/mL) 5249.5 (47) 2375.4 (41) tmax (h) median (range) 0.7 (0.7-1.25) 0.8 (0.7-1.3) t1/2 (h) 9.8 (32)n=22; 11.4 (36)n=21 AUC area under the curve, - last quantifiable sampleCmax maximum plasma concentration,tmax time at maximum plasma concentration,t1/2 half-life,Following continuous dosing with once-daily administration of estradiol and norethindrone acetate tablets 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 estradiol and norethindrone acetate tablets 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 Estradiol and Norethindrone Acetate Tablets mg/0.5 mg (N=24)Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of Estradiol and Norethindrone Acetate Tablets mg/0.5 mg (N=24)DistributionEstradiolThe 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%). MetabolismEstradiolExogenous 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 estradiol and norethindrone acetate tablets mg/0.5 mg is 12 to 14 hours.Norethindrone Acetate The terminal half-life of norethindrone is about to 11 hours. Figure 1a. Figure 1b.

SPL UNCLASSIFIED SECTION.

Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable DementiaThe 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 and 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)]. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 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)]. Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.Estrogen-Alone Therapy Endometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestogen 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 DementiaThe 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 and 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)]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oEstrogens increase the risk of gall bladder disease (5.4) oDiscontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10)oMonitor thyroid function in women on thyroid replacement therapy (5.11, 5.18). oEstrogens increase the risk of gall bladder disease (5.4) oDiscontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10). oMonitor thyroid function in women on thyroid replacement therapy (5.11, 5.18). 5.1 Cardiovascular Disorders. Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or is suspected.Manage appropriately any 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). Stroke The WHI estrogen plus progestin substudy reported statistically significant increased risk of stroke 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 strokes per 10,000 women-years) [see Clinical Studies (14.5)]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen with or without progestogen therapy if stroke occurs or is suspected.The WHI estrogen-alone substudy reported statistically significant increased risk of stroke 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 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year and persisted [see Clinical Studies (14.5)]. Immediately discontinue estrogen-alone therapy if stroke occurs or is suspected.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 Disease The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in those 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).1 An 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)]. The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo [see Clinical Studies (14.5)]. Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest reduction (not statistically significant) in CHD events in those women receiving daily CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years).1 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 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 Thromboembolism The WHI estrogen plus progestin substudy reported statistically significant 2-fold greater rate of VTE (DVT and PE) 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)]. Immediately discontinue estrogen plus progestogen therapy if VTE occurs or is suspected. 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)]. Immediately discontinue estrogen-alone therapy if VTE occurs or is suspected.If feasible, discontinue estrogens 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 Cancer After mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo.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. 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 groups [see Clinical Studies (14.5)]. The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. 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) 0.80] compared to placebo6 [see Clinical Studies (14.5)]. Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and smaller increase in the risk for breast cancer with 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. These studies have not generally 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 therapy 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 estradiol and norethindrone acetate tablets 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 Cancer 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 2-to 12-fold 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 progestogen therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology.There is no evidence that the use of natural estrogens results in different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer.Endometrial hyperplasia occured at rate of approximately percent or less with estradiol and norethindrone acetate tablets in clinical trial.Ovarian Cancer The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the 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 confidence interval [CI], 0.77-3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was versus cases per 10,000 women-years7 meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% CI 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than years [median of years] vs. greater than years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.. 5.3 Probable Dementia. In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, 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 group 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, 1.21-3.48). 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, 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, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years [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, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies (14.6)]. 5.4 Gallbladder Disease. 2-to 4-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 women with breast cancer and bone metastases. Discontinue estrogens, including estradiol and norethindrone acetate tablets if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level. 5.6 Vision Abnormalities. Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue estradiol and norethindrone acetate tablets pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including estradiol and norethindrone acetate tablets, if examination reveals papilledema or retinal vascular lesions. 5.7 Addition of Progestogen When Woman Has Not Had Hysterectomy. Studies of the addition of progestogen 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 progestogens 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 Exacerbation of Hypertriglyceridemia. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue estradiol and norethindrone acetate tablets if pancreatitis occurs.. 5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice. Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue estradiol and norethindrone acetate tablets.. 5.11 Exacerbation of 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. Monitor thyroid function in these women during treatment with estradiol and norethindrone acetate tablets to maintain their free thyroid hormone levels in an acceptable range.. 5.12 Fluid Retention. Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen plus progestogen therapy, including estradiol and norethindrone acetate tablets, with evidence of medically concerning fluid retention.. 5.13 Hypocalcemia. Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including estradiol and norethindrone acetate tablets, outweigh the risks in such women.. 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. 5.15 Hereditary Angioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including estradiol and norethindrone acetate tablets, outweigh the risks in such women. 5.16 Exacerbation of Other Conditions. Estrogen therapy, including estradiol and norethindrone acetate tablets, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in such women.. 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. oAccelerated 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. oIncreased thyroid-binding globulin (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. oOther 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). oIncreased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentration, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels. oImpaired glucose tolerance.. oAccelerated 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. oIncreased thyroid-binding globulin (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. oOther 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). oIncreased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentration, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels. oImpaired glucose tolerance.