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Pregnancy

8.1 Pregnancy Jinteli 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.

Drug Interactions

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted for Jinteli. •Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1) 7.1 Effect of Other Drugs on Combined Hormonal Products Substances decreasing or increasing the plasma concentration of estrogen: In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may decrease the plasma concentration of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase the plasma concentration of estrogens and may result in side effects. Co-administration of atorvastatin and certain hormonal products containing ethinyl estradiol increase AUC values for ethinyl estradiol approximately 20 percent. Ascorbic acid and acetaminophen may increase the plasma ethinyl estradiol concentration, possibly by inhibition of conjugation. 7.2 Effect of Combined Hormonal Products on Other Drugs Combination hormonal products containing some synthetic estrogens (for example, ethinyl estradiol) may inhibit the metabolism of other compounds. Combination hormonal products have been shown to significantly decrease the plasma concentration of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Indications And Usage

1 INDICATIONS AND USAGE Jinteli is an estrogen plus progestin indicated in a woman with a uterus for: •Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1) • Prevention of Postmenopausal Osteoporosis (1.2) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

Clinical Studies

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes per day upon study entry. A total of 66 women were randomized to receive Jinteli 1/5 and 66 women were randomized to the placebo group. Jinteli 1/5 was shown to be statistically better than placebo at weeks 4, and 12 for relief of the frequency of moderate to severe vasomotor symptoms (see Table 3). In Table 4 , Jinteli 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms. Table 3. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF Visit Placebo (N = 66) Jinteli 0.5/2.5 (N = 67) Jinteli 1/5 (N = 66) Baseline The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week pre-randomization observation period. Mean (SD) 76.5 (21.4) 77.6 (26.5) 70.0 (16.6) Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI)ANCOVA – Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI- Mann- Whitney confidence interval for the difference between means (not stratified by center). 39.4 (27.6) -37 (26.6) 30.2 (26.1) -47.4Denotes statistical significance at the 0.05 level (26.1) 0.041 (-20.0, -1.0) 20.4 (22.7) -49.6 (22.1) <0.001 (-22.0,-6.0) Week 12 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) 31.1 (27.0) -45.3 (30.2) 13.8 (20.4) -63.8 (27.5) <0.001 (-27, -7) 11.3 (18.9) -58.7 (23.1) <0.001 (-25, -5) ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized subjects (1 in Placebo and 1 in Jinteli) did not return diaries. Table 4. Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF Visit Placebo (N = 66) Jinteli 0.5/2.5 (N = 67) Jinteli 1/5 N = 66 Baseline The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week pre-randomization observation period. Mean (SD) 2.49 (0.26) 2.48 (0.22) 2.47 (0.23) Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI)ANCOVA – Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI- Mann- Whitney confidence interval for the difference between means (not stratified by center). 2.13 (0.74) -0.36 (0.68) - 1.88 (0.89) -0.59 (0.83) 0.13 (0.3, 0.0) 1.45 (1.03) -1.02Denotes statistical significance at the 0.05 level (1.06) <0.001 (-0.9, -0.2) Week 5 Mean (SD) Mean Change from Baseline (SD) p -Value vs. Placebo (95 percent CI) 2.06 (0.79) -0.44 (0.74) - 1.68 (0.99) -0.80 (0.94) 0.041 (-0.4, -0.0) 1.23 (1.03) -1.24 (1.07) <0.001 (-1.2, -0.3) Week 12 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) 1.82 (1.03) -0.67 (1.02) - 1.22 (1.11) -1.26 (1.08) 0.002 (-0.9, -0.2) 1.02 (1.16) -1.45 (1.19) <0.001 (-1.4, -0.3) ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized subjects (1 in Placebo and 1 in Jinteli) did not return diaries. 14.2 Effects on the Endometrium A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of Jinteli on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1,265 women were enrolled and randomized to either placebo, 0.2 mg NA/1 mcg ethinyl estradiol (NA/EE 0.2/1), 0.5 mg NA/2.5 mcg EE (NA/EE 0.5/2.5), Jinteli 1/5 and 1 mg NA/10 mcg EE (NA/EE 1/10) or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1,265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to Jinteli 1/5, 136 to NA/EE 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 Jinteli 1/5, 136 NA/EE 0.5/2.5, 139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95 percent of subjects), or insufficient tissue (in approximately 5 percent of subjects). Follow-up biopsies were obtained in approximately 70 to 80 percent of patients in each arm after 12 and 24 months of therapy. Results for Jinteli 1/5 and appropriate comparators are shown in Table 5. Table 5. Endometrial Biopsy Results After 12 and 24 Months of Treatment (CHART Study, 376- 359) Endometrial Status Placebo Jinteli EE Alone 0.5/2.5 1/5 2.5 mcg 5 mcg Number of Patients Biopsied at Baseline N = 134 N = 136 N = 143 N = 137 N = 139 MONTH 12 (Percent Patients) Patients Biopsied (percent) Insufficient Tissue Atrophic Tissue Proliferative Tissue Endometrial HyperplasiaAll patients with endometrial hyperplasia were carried forward for all time points. 113 (84) 30 60 23 0 103 (74) 34 41 28 0 110 (77) 45 41 24 0 100 (73) 20 15 65 0 114 (82) 20 2 91 1 MONTH 24 (Percent Patients) Patients Biopsied (percent) Insufficient Tissue Atrophic Tissue Proliferative Tissue Endometrial Hyperplasia 94 (70) 35 38 20 1 99 (73) 42 30 27 0 102 (71) 37 33 32 0 89 (65) 23 6 60 0 107 (77) 17 2 86 2 14.3 Effects on Uterine Bleeding or Spotting The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from subject recall, was evaluated over 12 months for Jinteli 1/5 and placebo arms. Results are shown in Figure 2. Figure 2. Patients With Cumulative Amenorrhea Over Time: Intent-to-Treat Population, Last Observation Carried Forward Figure 2 14.4 Effect on Bone Mineral Density In the 2 year study, trabecular BMD was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, 40 to 64 years of age, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to Jinteli 1/5, NA/EE 0.5/2.5 or placebo. Approximately 75 percent of the subjects in each group completed the two-year study. All patients received 1000 mg calcium in divided doses. Vitamin D was not supplemented. As shown in Figure 3, women treated with Jinteli 1/5 had an average increase of 3.1 percent in lumbar spine BMD from baseline to Month 24. Women treated with placebo had average decreases of -6.3 percent in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the Jinteli 1/5 group compared with the placebo group was statistically significant. Figure 3. Mean Percent Change (+ SE) From Baseline in Volumetric Bone Mineral Density* at Lumbar Spine Measured by Quantitative Computed Tomography after 12 and 24 Months of Treatment (Intent-to-Treat Population) *It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT. Figure 3 14.5 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi . Results are based on centrally adjudicated data. Event Relative Risk CE/MPA vs. Placebo (95 percent nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women -Years CHD events 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 cancer. Colorectal cancer Endometerial cancer Cervical cancer Hip fracture Vertebral fractures Lower arm/wrist fractures Total fractures Overall Mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. Global IndexA subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.23 (0.99 to 1.53) 1.28 (1.00 to 1.63) 1.10 (0.70 to 1.75) 1.31 (1.03 to 1.68) 1.44 (1.09 to 1.90) 1.95 (1.43 to 2.67) 2.13 (1.45 to 3.11) 1.24 (1.01 to 1.54) 0.61 (0.42 to 0.87) 0.81 (0.48 to 1.36) 1.44 (0.47 to 4.42) 0.67 (0.47 to 0.96) 0.65 (0.46 to 0.92) 0.71 (0.59 to 0.85) 0.76 (0.69 to 0.83) 1.00 (0.83 to 1.19) 1.13 (1.02 to 1.25) 41 31 8 33 26 26 18 41 10 6 2 11 11 44 152 52 184 34 25 8 25 18 13 8 33 16 7 1 16 17 62 199 52 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44 to 1.07)]. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was also stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in Table 7. Table 7. Relative and Absolute Risk Seen in the Estrogen- Alone Substudy of WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nblbi.nih.gov/whi . Event Relative Risk CE vs Placebo (95 percent nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women -Years CHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years. Non-fatal MI CHD death All strokes Ischemic stroke Deep vein thrombosis Not included in “global index”. Pulmonary embolism Invasive breast cancer Colorectal cancerResults are based on an average follow-up of 6.8 years. Hip fracture Vertebral fractures Lower arm/wrist fractures Total fractures Deaths due to other causes All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. Overall Mortality Global IndexA subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 0.95 (0.78 to 1.16) 0.91 (0.73 to 1.14) 1.01 (0.71 to 1.43) 1.33 (1.05 to 1.68) 1.55 (1.19 to 2.01) 1.47 (1.06 to 2.06) 1.37 (0.90 to 2.07) 0.80 (0.62 to 1.04) 1.08 (0.75 to 1.55) 0.65 (0.45 to 0.94) 0.64 (0.44 to 0.93) 0.58 (0.47 to 0.72) 0.71 (0.64 to 0.80) 1.08 (0.88 to 1.32) 1.04 (0.88 to 1.22) 1.02 (0.92 to 1.13) 54 40 16 45 38 23 14 28 17 12 11 35 144 53 79 206 57 43 16 33 25 15 10 34 16 19 18 59 197 50 75 201 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 were 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years (see Table 7). 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 therapy increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined10 (see Table 7). Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)]. 14.6 Women’s Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3), and Use in Specific Populations (8.5)]. The WHIMS estrogen-alone ancillary study of WHI 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 to 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 to 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)].

Warnings And Cautions

5 WARNINGS AND PRECAUTIONS •Estrogens increase the risk of gallbladder 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. Stroke In the WHI estrogen plus progestin substudy, a 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.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily conjugated estrogens 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 1 and persisted [see Clinical Studies ( 14.5)]. Should a 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).1 Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased 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).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [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 placebo2 [see Clinical Studies ( 14.5)]. Subgroup analyses of women 50 to 59 years of age suggest a 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 woman-years).1 In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a 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 a 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 In the WHI estrogen plus progestin substudy, a 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 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted3 [see Clinical Studies ( 14.5)]. Should a 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 2 years4 [see Clinical Studies ( 14.5)]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism or during periods of prolonged immobilization. 5.2 Malignant Neoplasms Breast Cancer The 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 a 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 a 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] 0.80 [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 a 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 5 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. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results. Endometrial Cancer Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1 percent or less with Jinteli. An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 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 a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Ovarian Cancer The WHI estrogen plus progestin substudy reported a 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 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 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, a 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 4 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 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-years8 [see Use in Specific Populations ( 8.5), and Clinical Studies (14.6)]. In the WHIMS estrogen-alone ancillary study of WHI, a 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 for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Since both ancillary substudies 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 A 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. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 5.6 Visual Abnormalities Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. 5.7 Addition of a Progestin When a Woman Has Not Had a Hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a 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 a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a 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 a Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with impaired liver function. For women with a 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 in order 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 A 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. 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 antigen, VIII coagulant activity, IX, X, XII, VII-X complex, IIVII-X complex, and beta-thromboglobulin; decreased levels of antifactor 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. Jinteli 1/5 was associated with an SHBG increase of 22 percent. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance.

Overdosage

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 Jinteli with institution of appropriate symptomatic care.

Adverse Reactions

6 ADVERSE REACTIONS 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)]. Most common adverse reactions (incidence greater than or equal to 5 percent) are headache, abdominal pain, breast pain, and edema (generalized). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 by ≥5 percent of subjects in controlled clinical studies of Jinteli are shown in Table 1. Table 1. Associated Adverse Reactions Reported by ≥5 Percent of Subjects by Body System The total number of subjects for each body system may be less than the number of subjects with AEs in that body system because a subject may have had more than one AE per body system BODY SYSTEM/ Adverse Reaction Number (Percent) of Subjects Placebo N = 247 Jinteli 0.5/2.5 N = 244 Jinteli 1/5 N = 258 BODY AS A WHOLE Edema – Generalized Headache 23 (12.8) 10 (4.0) 12 (4.9) 30 (16.9) 12 (4.9) 14 (5.7) 30 (15.7) 11 (43) 16 (6.2) DIGESTIVE SYSTEM Abdominal Pain 8 (4.4) 3 (1.2) 17 (9.6) 13 (5.3) 25 (13.1) 14 (6.8) UROGENITAL SYSTEM Breast Pain 20 (11.1) 9 (3.6) 34 (19.2) 22 (9.0) 45 (23.6) 20 (7.8) 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Jinteli. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer; uterine cancer; vaginal hemorrhage; ovarian cyst; irregular menstruation; metrorrhagia; menorrhagia; dysmenorrhea; uterine enlargement. Breasts Tenderness, enlargement, breast pain, nipple pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer; breast disorder; breast mass; breast enlargement. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; thrombosis; chest pain; myocardial infarction; cerebrovascular accident (stroke); transient ischemic attack; hemiparesis; increase in blood pressure; irregular heart rate; palpitations; dyspnea. Gastrointestinal Nausea, vomiting; cholestatic jaundice; pancreatitis, enlargement of hepatic hemangiomas; bloating, abdominal cramps; abdominal pain; increased incidence of gallbladder disease; cholecystitis; cholelithiasis. Skin Chloasma or melasma that may persist when drug is discontinued; generalized erythema; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; rash, pruritus. Eyes Retinal vascular thrombosis; visual impairment; intolerance to contact lenses. Central Nervous System (CNS) Headache; migraine; dizziness; depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia; paresthesia; insomnia. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; back pain; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides; blood glucose abnormal; fatigue; myalgia; hypersensitivity.

Mechanism

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 a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is 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. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Contraindications

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

Nursing Mothers

8.3 Nursing Mothers Jinteli 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 Jinteli is administered to a nursing woman.