PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption. Serum concentrations of DRSP reach peak concentrations approximately hour after administration of Angeliq and mean absolute bioavailability of DRSP ranges from 76-85%. Following oral administration, the median Tmax of serum estradiol was approximately hours after dosing with Angeliq and Tmax ranged between 0.3-10 hours. The pharmacokinetics of DRSP are dose proportional within the dose range of 0.25-4 mg. Following daily dosing of Angeliq, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for DRSP and estradiol were 2.3 and 2.0, respectively, following multiple doses of 0.5 mg DRSP/1 mg E2, and 2.6 and 1.6, respectively, following multiple doses of 0.25 mg DRSP/0.5 mg E2. Mean concentrations at hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with Angeliq (0.5 mg DRSP/1 mg E2) for 365 days. Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and summary of primary pharmacokinetic parameters following the administration of 0.25 mg DRSP/0.5 mg E2 or 0.5 mg DRSP/1 mg E2 at steady state is presented in Table 3.Figure 1: Mean (+- SD) steady state serum drospirenone and estradiol concentrations following daily oral administration of 0.25 or 0.5 mg Drospirenone and 0.5 or mg EstradiolTable 3: Mean (+- SD) Steady State Pharmacokinetic Parameters after Administration of Tablets Containing 0.25 or 0.5 mg Drospirenone and 0.5 or mg Estradiol ParameterUnit0.25 mg DRSP/0.5 mg E20.5 mg DRSP/1 mg E2Drospirenone (DRSP)N=12N=17Cmax ng/mL5.70 (1.42)8.50 (1.63)Tmax h0.992 (0.667 1.03)1.02 (1 2.03)AUC (0-24)ng.h/mL48.5 (13.7)84.3 (19.7)t1/2 hN/A39.2N=16(8.5)Estradiol (E2)Cmax pg/mL29.7 (6.80)63.7 (24.2)Tmax h2.33 (0.32 10)2.01 (0.5 6.02)AUC (0-24)pg.h/mL515.4 (142.0)882 (267)t1/2 hN/A20.5 (2.67)Estrone (E1)Cmax pg/mL165.7 (40.4)362 (122)Tmax h3.98 (1.98 7.05)6 (3.99 10)AUC (0-24)pg.h/mL2839 (658)5561 (1689)t1/2 hN/A19.9 (2.10)Except for Tmax, the mean PK results of DRSP, E2, and E1 are displayed as the arithmetic mean and standard deviation (SD, in parentheses). For Tmax the median and range are provided.Cmax=Maximum observed serum concentrationTmax=time to reach Cmax AUC (0-24)=area under the serum concentration-time curve from h up to 24 after daily multiple administrationt1/2=half-lifeN/A=Not available. Figuree 1. Effect of Food. The effect of food on the absorption and bioavailability of DRSP and E2 have not been investigated following the administration of Angeliq. However, clinical studies with different formulations containing DRSP or E2 have shown that the bioavailability of both drugs is not affected by concomitant food intake. Distribution The mean volume of distribution of DRSP is 4.2 L/kg. DRSP does not bind to SHBG or CBG but binds about 97% to other serum proteins. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1%-2% is unbound. Metabolism. Mean clearance of DRSP is 1.2 mL/min/kg. DRSP is extensively metabolized after oral administration. The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active. DRSP is also subject to oxidative metabolism catalyzed by CYP3A4. Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut 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. ExcretionDRSP serum concentrations are characterized by terminal elimination half-life of approximately 36-42 hours. Excretion of DRSP was nearly complete after 10 days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38% to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17% to 20% of the metabolites were excreted as glucuronides and sulfates. Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Use in Specific Populations Geriatric. No pharmacokinetic studies were conducted for Angeliq in the geriatric population. Pediatric. No pharmacokinetic studies were conducted for Angeliq in pediatric population. Gender. Angeliq is indicated for use in women only. Race. No studies were done to determine the effect of race on the pharmacokinetics of Angeliq. Hepatic Impairment. Angeliq is contraindicated in patients with hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.10)]. The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function. Renal Impairment. Angeliq is contraindicated in patients with renal impairment [see Contraindications (4) and Warnings and Precautions (5.2)]. The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effects of DRSP on serum potassium concentrations were investigated in female subjects (n=28, age 30-65 years) with creatinine clearance (CLcr) >= 80 mL/min (11 patients), and CLcr of 50-79 mL/min (10 patients) and CLcr of 30-49 mL/min (7 patients). All subjects were on low potassium diet. During the study subjects continued the use of potassium-sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations were on average 37% higher in the group with CLcr of 30-49 mL/min compared to those in the group with normal renal function (CLcr >= 80 mL/min). Serum DRSP concentrations in the group with CLcr of 50-79 mL/min were comparable to those in the group with CLcr >= 80 mL/min. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in of the subjects who continued use of potassium sparing drugs during the study, individual mean serum potassium concentrations increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.. Drug Interactions. No formal drug interaction studies have been conducted for Angeliq.Effects of Drospirenone on Other Drugs: Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies, DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in clinical pharmacokinetic study using omeprazole as marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of mg DRSP for 14 days did not affect the systemic clearance of the CYP2C19 substrate omeprazole (40 mg) and the CYP2C19 product 5-hydroxy-omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo. Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy, postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations achieved after administration of mg DRSP/day.Based on the available results of in vivo and in vitro studies, it can be concluded that, at clinical dose concentration, DRSP is unlikely to inhibit significantly CYP enzymes.There is potential for an increase in serum potassium in women taking drospirenone with other drugs that may affect electrolytes, such as ACE inhibitors, angiotensin receptor blockers, or NSAIDs. Electrolytes were studied in 230 postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker. Of these, 26 patients had creatinine clearance >50 mL/min to <80 mL/min. Patients were given mg E2 and mg DRSP (n=112) or placebo (n=118) over 28 days. Non-diabetic patients also received ibuprofen 1200 mg/day for days during the study. There was single case of serum potassium >6 mEq/L and single case of serum sodium <130 mEq/L on treatment, both occurring following five days of ibuprofen therapy in two women taking E2/DRSP. Serum potassium concentrations >=5.5 mEq/L were observed in (7.3%) E2/DRSP-treated subjects (3 diabetic and non-diabetic) and in (2.6%) placebo-treated subjects (2 diabetic and non-diabetic). After 28 days of exposure, the mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium concentrations >=5.5 mEq/L had cardiovascular adverse events. drug-drug interaction study of DRSP mg/E2 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for total of weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L). Of note, occasional or chronic use of NSAID medication was not restricted in any of the Angeliq clinical trials.Effects of Other Drugs on Estrogens and Progestins: In vitro and in vivo studies have shown that estrogens and progestins are metabolized partially by CYP3A4. Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism [see Drug Interactions (7.1)]. In clinical drug-drug interaction study conducted in 18 premenopausal women, once daily co-administration of DRSP mg/E2 1.5 mg combination tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in 2.30-fold (90% CI: 2.08-2.54) increase of the AUC (0-24) and 1.66-fold (90% CI: 1.50-1.84) increase of Cmax for DRSP. The E2 exposure [that is, AUC (0-24) and Cmax] was unaffected by ketoconazole, although the AUC(0-24) and Cmax for E1 increased 1.39-fold (90% CI: 1.27-1.52) and 1.32-fold (90% CI: 1.23-1.42), respectively.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No formal drug-drug interaction studies have been conducted for Angeliq.. oInducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration (7.1)oSerum potassium concentration may increase in women taking drospirenone with other drugs that have the potential to increase potassium (7.1). oInducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration (7.1). oSerum potassium concentration may increase in women taking drospirenone with other drugs that have the potential to increase potassium (7.1). 7.1 Metabolic Interactions. Effect of Drospirenone on Other Drugs. The potential effect of DRSP on CYP2C19 activity was investigated in clinical pharmacokinetic study using omeprazole as marker substrate. No significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo. Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4, respectively, were performed and the results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations.Co-administration of DRSP and drugs that may increase serum potassium: There is potential for an increase in serum potassium in women taking DRSP with other drugs that may affect electrolytes, such as ACE inhibitors, angiotensin receptor blockers, or NSAIDs, more pronounced in diabetic women [see Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)]. Electrolytes were studied in postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker. After 28 days of exposure to mg E2 and mg DRSP (n=112) or placebo (n=118). The mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium concentrations >=5.5 mEq/L had cardiovascular adverse events. drug-drug interaction study of DRSP mg/E2 mg versus placebo was performed in mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for total of weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L). Of note, occasional or chronic use of NSAID medication was not restricted in any of the Angeliq clinical trials.. Effect of Other Drugs on Estrogens and Progestins. In vitro and in vivo studies have shown that estrogens and progestins are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. In clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP mg/E2 1.5 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in moderate increase of exposure and mild increase of peak concentration for DRSP. The E2 exposure and peak concentration were unaffected by ketoconazole, although the exposure and peak concentration of estrone (E1) increased. Although no clinically relevant effects on any safety or laboratory parameters including serum potassium were observed, this study only assessed subjects for 10 days. The clinical impact for woman taking DRSP-containing combination hormone and chronic use of CYP3A4/5 inhibitor is unknown.. Substances decreasing the exposure and possibly diminishing the efficacy of estrogens and progestins (enzyme inducers) Inducers of CYP3A4 such as St. Johns wort (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens and progestins, possibly resulting in decrease in therapeutic effects and/or changes in the uterine bleeding profile.. Substances increasing the exposure of estrogens and progestins (enzyme inhibitors) Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit juice did increase the plasma concentrations of the estrogen or the progestin or both [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. 7.2 Interaction with Alcohol. Acute alcohol ingestion during use of hormone therapy may lead to elevations of circulating E2 concentrations.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:oCardiovascular Disorders [see Boxed Warning, and Warnings and Precautions (5.1)]oMalignant Neoplasms [see Boxed Warning, and Warnings and Precautions (5.3)]. oCardiovascular Disorders [see Boxed Warning, and Warnings and Precautions (5.1)]. oMalignant Neoplasms [see Boxed Warning, and Warnings and Precautions (5.3)]. The most common adverse reactions that occurred in at least percent of users in clinical trials with Angeliq are gastrointestinal and abdominal pain, female genital tract bleeding, breast pain and discomfort, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. From clinical trials with different dose formulations of Angeliq containing E2 dose ranging from 0.5 mg to 1.0 mg combined with DRSP dose ranging from 0.25 mg to mg:oThe most common adverse reactions were gastrointestinal and abdominal pain, female genital bleeding, breast pain and headache. The frequencies of common adverse reactions, in general, were higher for the Angeliq dose formulation containing E2 mg compared to Angeliq containing E2 0.5 mg.oThe most common adverse reactions leading to drug discontinuation in controlled clinical trials were abdominal pain, headache, postmenopausal bleeding, breast tenderness, and weight increased.. oThe most common adverse reactions were gastrointestinal and abdominal pain, female genital bleeding, breast pain and headache. The frequencies of common adverse reactions, in general, were higher for the Angeliq dose formulation containing E2 mg compared to Angeliq containing E2 0.5 mg.. oThe most common adverse reactions leading to drug discontinuation in controlled clinical trials were abdominal pain, headache, postmenopausal bleeding, breast tenderness, and weight increased.. Placebo-Controlled Trial:. In placebo-controlled trial evaluating Angeliq 0.25 mg DRSP/0.5 mg E2, 183 postmenopausal women received at least one dose of DRSP 0.25 mg/0.5 mg E2 and 180 received placebo. Study subjects were treated for cycles of 28 days each for total of 12 weeks of treatment. The median age was 53 years (range: 40-77 years) and over 50% of subjects had hysterectomy, 68% were Caucasian and 24% were Black. Table summarizes adverse reactions reported in at least 2% of subjects receiving Angeliq 0.25 mg DRS/0.5 mg E2 and at higher incidence than subjects receiving placebo.Table 1: Adverse Reactions that Occurred at Frequency of >= 2% with Angeliq 0.25 mg DRSP/0.5 mg E2 and at higher incidence than placeboAdverse ReactionAngeliq(0.25 mg DRSP/0.5 mg E2)N=183 (100%)n (%)Placebo N=180 (100%)n (%)Gastrointestinal and abdominal painsGastrointestinal and abdominal pain includes: abdominal pain (overall, lower, and upper), abdominal discomfort, abdominal tenderness 11 (6.0)5 (2.8)Headache11 (6.0)9 (5.0)Vulvovaginal fungal infections10 (5.5)1 (0.6)Breast painBreast pain includes: breast pain, breast tenderness, nipple pain (3.3)1 (0.6)Nausea (3.3)2 (1.1)Diarrhea 2.2)1 (0.6)Peripheral Edema (2.2)2 (1.1). Pooled data of clinical trials with different dose formulations of Angeliq:. Data from 13 clinical trials in postmenopausal subjects treated with different dose formulations of Angeliq containing mg E2 (1 mg E2 0.5 mg 3.0 mg DRSP; N=2842) were pooled to provide an overall estimate of adverse reactions. Similarly, data from clinical trials with Angeliq containing 0.5 mg E2 (0.5 mg E2 DRSP 0.25 mg 0.5 mg; N=853) were pooled for the same purpose. Table shows adverse reactions reported in at least 1% of subjects treated with Angeliq.Table 2: Adverse Reactions that Occurred at Frequency of >= 1% in Clinical TrialsAdverse ReactionAngeliq containing mg E2 = 2842n (%)Angeliq containing 0.5 mg E2 N=853n (%)Breast pain or discomfort508 (17.9)53 (6.2)Female genital tract bleeding 397 (14.0)21 (2.5)Gastrointestinal and abdominal pain186 (6.5)31 (3.6)Cervical polyp34 (1.2)3 (0.4)Emotional lability35 (1.2)11 (1.3)Migraine28 (1.0)5 (0.6)Adverse Reactions in clinical studies were coded using the MedDRA dictionary (version 13.0). Different MedDRA terms representing the same medical phenomenon have been grouped together as single adverse reactions to avoid diluting or obscuring the true effect.. 6.2 Postmarketing Experience. The following additional adverse reactions have been reported during post approval use of Angeliq. Because these reactions are reported voluntarily from population of uncertain size, reliably estimating their frequency or establishing causal relationship to drug exposure is not always possible.Immune System Disorders: Hypersensitivity reactions, including rash, pruritis, and urticariaReproductive system and breast disorders: Breast cancerVascular disorders: venous and arterial thromboembolic events (peripheral deep venous occlusion, thrombosis and embolism/pulmonary vascular occlusion, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and stroke not specified as hemorrhagic).

BOXED WARNING SECTION.

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA. Estrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.4) and Clinical Studies (14.4, 14.5)]. The Womens Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk 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 estrogens (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 WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions 5.4) Use in Specific Populations (8.5), and Clinical Studies (14.5)]. Breast CancerThe WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.3), and Clinical Studies (14.4)].In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.3)].Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.4) and Clinical Studies (14.5, 14.4)]. The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)]. The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4), Use in Specific Populations (8.5), and Clinical Studies (14.5)].In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.. WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIASee full prescribing information for complete boxed warningEstrogen Plus Progestin TherapyoEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.4 )oThe Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (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 (5.4)Estrogen-Alone TherapyoThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.3)oEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.4)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 (5.4). oEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.4 ). oThe Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (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 (5.4). oThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.3). oEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.4). 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 (5.4).

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 (E2) 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, estrogen receptors have been identified. These will. 12.2 Pharmacodynamics. No clinical pharmacology studies have been conducted for Angeliq.. 12.3 Pharmacokinetics. Absorption. Serum concentrations of DRSP reach peak concentrations approximately hour after administration of Angeliq and mean absolute bioavailability of DRSP ranges from 76-85%. Following oral administration, the median Tmax of serum estradiol was approximately hours after dosing with Angeliq and Tmax ranged between 0.3-10 hours. The pharmacokinetics of DRSP are dose proportional within the dose range of 0.25-4 mg. Following daily dosing of Angeliq, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for DRSP and estradiol were 2.3 and 2.0, respectively, following multiple doses of 0.5 mg DRSP/1 mg E2, and 2.6 and 1.6, respectively, following multiple doses of 0.25 mg DRSP/0.5 mg E2. Mean concentrations at hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with Angeliq (0.5 mg DRSP/1 mg E2) for 365 days. Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and summary of primary pharmacokinetic parameters following the administration of 0.25 mg DRSP/0.5 mg E2 or 0.5 mg DRSP/1 mg E2 at steady state is presented in Table 3.Figure 1: Mean (+- SD) steady state serum drospirenone and estradiol concentrations following daily oral administration of 0.25 or 0.5 mg Drospirenone and 0.5 or mg EstradiolTable 3: Mean (+- SD) Steady State Pharmacokinetic Parameters after Administration of Tablets Containing 0.25 or 0.5 mg Drospirenone and 0.5 or mg Estradiol ParameterUnit0.25 mg DRSP/0.5 mg E20.5 mg DRSP/1 mg E2Drospirenone (DRSP)N=12N=17Cmax ng/mL5.70 (1.42)8.50 (1.63)Tmax h0.992 (0.667 1.03)1.02 (1 2.03)AUC (0-24)ng.h/mL48.5 (13.7)84.3 (19.7)t1/2 hN/A39.2N=16(8.5)Estradiol (E2)Cmax pg/mL29.7 (6.80)63.7 (24.2)Tmax h2.33 (0.32 10)2.01 (0.5 6.02)AUC (0-24)pg.h/mL515.4 (142.0)882 (267)t1/2 hN/A20.5 (2.67)Estrone (E1)Cmax pg/mL165.7 (40.4)362 (122)Tmax h3.98 (1.98 7.05)6 (3.99 10)AUC (0-24)pg.h/mL2839 (658)5561 (1689)t1/2 hN/A19.9 (2.10)Except for Tmax, the mean PK results of DRSP, E2, and E1 are displayed as the arithmetic mean and standard deviation (SD, in parentheses). For Tmax the median and range are provided.Cmax=Maximum observed serum concentrationTmax=time to reach Cmax AUC (0-24)=area under the serum concentration-time curve from h up to 24 after daily multiple administrationt1/2=half-lifeN/A=Not available. Figuree 1. Effect of Food. The effect of food on the absorption and bioavailability of DRSP and E2 have not been investigated following the administration of Angeliq. However, clinical studies with different formulations containing DRSP or E2 have shown that the bioavailability of both drugs is not affected by concomitant food intake. Distribution The mean volume of distribution of DRSP is 4.2 L/kg. DRSP does not bind to SHBG or CBG but binds about 97% to other serum proteins. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1%-2% is unbound. Metabolism. Mean clearance of DRSP is 1.2 mL/min/kg. DRSP is extensively metabolized after oral administration. The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active. DRSP is also subject to oxidative metabolism catalyzed by CYP3A4. Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut 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. ExcretionDRSP serum concentrations are characterized by terminal elimination half-life of approximately 36-42 hours. Excretion of DRSP was nearly complete after 10 days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38% to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17% to 20% of the metabolites were excreted as glucuronides and sulfates. Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Use in Specific Populations Geriatric. No pharmacokinetic studies were conducted for Angeliq in the geriatric population. Pediatric. No pharmacokinetic studies were conducted for Angeliq in pediatric population. Gender. Angeliq is indicated for use in women only. Race. No studies were done to determine the effect of race on the pharmacokinetics of Angeliq. Hepatic Impairment. Angeliq is contraindicated in patients with hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.10)]. The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function. Renal Impairment. Angeliq is contraindicated in patients with renal impairment [see Contraindications (4) and Warnings and Precautions (5.2)]. The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effects of DRSP on serum potassium concentrations were investigated in female subjects (n=28, age 30-65 years) with creatinine clearance (CLcr) >= 80 mL/min (11 patients), and CLcr of 50-79 mL/min (10 patients) and CLcr of 30-49 mL/min (7 patients). All subjects were on low potassium diet. During the study subjects continued the use of potassium-sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations were on average 37% higher in the group with CLcr of 30-49 mL/min compared to those in the group with normal renal function (CLcr >= 80 mL/min). Serum DRSP concentrations in the group with CLcr of 50-79 mL/min were comparable to those in the group with CLcr >= 80 mL/min. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in of the subjects who continued use of potassium sparing drugs during the study, individual mean serum potassium concentrations increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.. Drug Interactions. No formal drug interaction studies have been conducted for Angeliq.Effects of Drospirenone on Other Drugs: Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies, DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in clinical pharmacokinetic study using omeprazole as marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of mg DRSP for 14 days did not affect the systemic clearance of the CYP2C19 substrate omeprazole (40 mg) and the CYP2C19 product 5-hydroxy-omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo. Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy, postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations achieved after administration of mg DRSP/day.Based on the available results of in vivo and in vitro studies, it can be concluded that, at clinical dose concentration, DRSP is unlikely to inhibit significantly CYP enzymes.There is potential for an increase in serum potassium in women taking drospirenone with other drugs that may affect electrolytes, such as ACE inhibitors, angiotensin receptor blockers, or NSAIDs. Electrolytes were studied in 230 postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker. Of these, 26 patients had creatinine clearance >50 mL/min to <80 mL/min. Patients were given mg E2 and mg DRSP (n=112) or placebo (n=118) over 28 days. Non-diabetic patients also received ibuprofen 1200 mg/day for days during the study. There was single case of serum potassium >6 mEq/L and single case of serum sodium <130 mEq/L on treatment, both occurring following five days of ibuprofen therapy in two women taking E2/DRSP. Serum potassium concentrations >=5.5 mEq/L were observed in (7.3%) E2/DRSP-treated subjects (3 diabetic and non-diabetic) and in (2.6%) placebo-treated subjects (2 diabetic and non-diabetic). After 28 days of exposure, the mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium concentrations >=5.5 mEq/L had cardiovascular adverse events. drug-drug interaction study of DRSP mg/E2 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for total of weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L). Of note, occasional or chronic use of NSAID medication was not restricted in any of the Angeliq clinical trials.Effects of Other Drugs on Estrogens and Progestins: In vitro and in vivo studies have shown that estrogens and progestins are metabolized partially by CYP3A4. Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism [see Drug Interactions (7.1)]. In clinical drug-drug interaction study conducted in 18 premenopausal women, once daily co-administration of DRSP mg/E2 1.5 mg combination tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in 2.30-fold (90% CI: 2.08-2.54) increase of the AUC (0-24) and 1.66-fold (90% CI: 1.50-1.84) increase of Cmax for DRSP. The E2 exposure [that is, AUC (0-24) and Cmax] was unaffected by ketoconazole, although the AUC(0-24) and Cmax for E1 increased 1.39-fold (90% CI: 1.27-1.52) and 1.32-fold (90% CI: 1.23-1.42), respectively.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Effects on Vasomotor Symptoms Angeliq 0.25 mg DRSP/0.5 mg E2. The efficacy of Angeliq 0.25 mg DRSP/0.5 mg E2 for reducing the frequency and severity of moderate to severe vasomotor symptoms was evaluated in randomized, double-blind, placebo-controlled trial. total of 735 postmenopausal women >= 40 years of age with minimum of to moderate to severe hot flashes daily or 50 to 60 moderate to severe hot flashes weekly were randomized to one of the two doses of Angeliq, including DRSP 0.25 mg/0.5 mg E2, estrogen monotherapy, or placebo. The median age of study subjects was 53 years and 68% were Caucasian. Efficacy for vasomotor symptoms was assessed during the 12 weeks of treatment. Compared to placebo, subjects receiving Angeliq 0.25 mg DRSP/0.5 mg E2 achieved statistically significant reduction in the frequency and severity of moderate to severe vasomotor symptoms at Week and at Week 12. The mean difference in daily reduction of frequency of hot flushes between Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo were approximately -2 episodes at Week and -3 episodes at Week 12. Table shows the mean number of hot flushes in the Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo groups and the treatment difference between Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo treatment at Week and at Week 12.Table 4: Summary Tabulation Of The Number Of Hot Flushes Per Day Mean Values And Comparisons Between the Active Treatment Group and the Placebo Group, Last Observation Carried ForwardTreatmentNo. of Hot Flushes/DayTime Period(week) BaselineMeanMean Change from BaselineMean change from baseline, difference from placebo, 95% confidence interval, and p-value based on an ANCOVA model with treatment and pooled center as factors and baseline measurement as covariate Difference from Placebo (95% CI)p-Valuesvs. Placebo DRSP/E2 (0.25 mg/0.5 mg) [n=175] Week 410.68-5.46-2.02 (-2.89, -1.16)<0.0001 Week 1210.68-7.71-3.17 (-3.97, -2.37)<0.0001Placebo [n=176] Week 410.53-3.44-- Week 1210.53-4.54--. Angeliq 0.5 mg DRSP/1 mg E2. Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bioequivalence of the E2 component of the Angeliq combination product with currently marketed mg E2 product. The multiple-dose bioequivalence study evaluated the bioequivalence of E2 from tablet containing DRSP (2 mg) and E2 (1 mg) relative to E2 mg tablet. Angeliq 0.5 mg DRSP/1 mg E2 tablets met the criteria for bioequivalence to the E2 mg comparator. 14.2 Effects on Endometrium. Angeliq 0.25 mg DRSP/0.5 mg E2. In one year clinical trial, 661 postmenopausal subjects were treated with Angeliq 0.25 mg DRSP/0.5 mg E2 (N=489) or comparator drug (N=172). Endometrial biopsies were performed on 407 (83.2%) subjects in the Angeliq group during the treatment period. No endometrial hyperplasias occurred during or after one year of treatment. See Table 5.. Angeliq 0.5 mg DRSP/1 mg E2. In one year clinical trial of 1,142 postmenopausal subjects treated with mg E2 alone or mg E2 0.5, 1, 2, or mg DRSP, endometrial biopsies were performed on 966 (84.6%) subjects during the treatment period. Eight subjects in the E2 monotherapy group developed endometrial hyperplasia (4 simple hyperplasia with no cytological atypia, complex hyperplasia with no cytological atypia, and complex hyperplasia with cytological atypia), and one subject in the mg E2+2 mg DRSP group developed simple hyperplasia with no cytological atypia. Table shows that there were no diagnoses of endometrial hyperplasia in the Angeliq group. Table 5: Incidence of Endometrial Hyperplasia after up to 12 Months of Treatment E2 mgAngeliq 0.25 mg DRSP/0.5 mg E2Angeliq 0.5 mg DRSP/1 mg E2Total No. Subjects Treated226489227Total No. of On-Treatment BiopsiesIncludes evaluable and unevaluable endometrial biopsy results197 (87.2%)407 (83.2%)191 (84.1%)Hyperplasia8 (4%)0 (0%)0 (0%). 14.3 Effects on Uterine Bleeding or Spotting Angeliq 0.5 mg DRSP/1 mg E2 and Angeliq 0.25 mg DRSP /0.5 mg E2 were evaluated in separate one-year clinical trials investigating the endometrial safety in postmenopausal women with an intact uterus.Over 12 months in the double-blind trials, the proportions of women with any bleeding or spotting decreased over time. At one year, approximately 22% of women treated with Angeliq 0.5 mg/E2 1.0 mg and 15% of women treated with Angeliq 0.25 mg/E2 0.5 mg had any uterine bleeding or spotting. See Figure 2.Figure 2: Proportion of Subjects with any Bleeding/Spotting by Month of Angeliq Use. Figure 2. 14.4 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 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 vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.) CE/MPA n=8,506 Placebo n=8,102 Absolute Risk per 10,000 Women-YearsCHD events1.23 (0.99-1.53)4134Non-fatal MI1.28 (1.02-1.632)3125 CHD death1.10 (0.70-1.75)88All strokes1.31 (1.03-1.68)3325Ischemic stroke1.44 (1.09-1.90)2618Deep vein thrombosisNot included in global index. 1.95 (1.43-2.67)2613Pulmonary embolism2.13 (1.45-3.11)188Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. 1.24 (1.01-1.54)4133Colorectal cancer0.61 (0.42-0.87)1016Endometrial cancer 0.81 (0.48-1.36)67Cervical cancer 1.44 (0.47-4.42)21Hip fracture 0.67 (0.47-0.96)1116Vertebral fractures 0.65 (0.46-0.92)1117Lower arm/wrist fractures 0.71 (0.59-0.85)4462Total fractures 0.76 (0.69-0.83)152199Overall MortalityAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19)5252Global 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)184165Timing of the initiation of estrogen 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 50-59 years of age, non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CT 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 age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 7.Table 7. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. EventRelative RiskCE vs. Placebo (95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CEn=5,310Placebon=5,429Absolute Risk per 10,000 Women-YearsCHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78-1.16)5457Non-fatal MI0.91 (0.73-1.14)4043CHD death1.01 (0.71-1.43)1616All stroke 1.33 (1.05-1.68)4533Ischemic1.55 (1.19-2.01)3825Deep vein thrombosis Not included in global index. 1.47 (1.06-2.06)2315Pulmonary embolism 1.37 (0.90-2.07)1410Invasive breast cancer 0.80 (0.62-1.04)2834Colorectal cancer 1.08 (0.75-1.55)1716Hip fracture 0.65 (0.45-0.94)1219Vertebral fractures 0.64 (0.44-0.93)1118Lower arm/wrist fractures 0.58 (0.47-0.72)3559Total fractures 0.71 (0.64-0.8)144197Death due to other causesResults are based on an average follow-up of 6.8 years. All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88-1.32)5350Overall Mortality 1.04 (0.88-1.22)7975Global 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)206201For 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.9 The absolute excess risk of events included in the global index was non-significant events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10 Timing of the initiation of estrogen 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 CT 0.46-1.11)].. 14.5 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, and 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 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 type (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 (5.4), 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 and older (45 percent were age 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) 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 type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and 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 (5.4) and Use in Specific Populations (8.5)].When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall RR 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 (5.4) and Use in Specific Populations (8.5)].

SPL PATIENT PACKAGE INSERT SECTION.

FDA-Approved Patient LabelingPATIENT INFORMATIONAngeliq(R) (anju-le-k) (drospirenone and estradiol)TabletsRead this Patient Information before you start taking Angeliq and each time you refill your Angeliq prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.. What is the most important information should know about Angeliq (combination of estrogen and progestin hormones)oDo not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (declines of brain function)oUsing estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots oUsing estrogens with progestins may increase your chance of getting dementia, based on study of women 65 years of age or olderoDo not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementiaoUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb)oUsing estrogen-alone may increase your chances of getting strokes or blood clotsoUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age or olderoYou and your healthcare provider should talk regularly about whether you still need treatment with Angeliq. oDo not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (declines of brain function). oUsing estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots oUsing estrogens with progestins may increase your chance of getting dementia, based on study of women 65 years of age or older. oDo not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia. oUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb). 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 or older. oYou and your healthcare provider should talk regularly about whether you still need treatment with Angeliq. What is AngeliqAngeliq is medicine that contains kinds of hormones, estrogen and progestin. oAngeliq 0.25 mg drospirenone (DRSP)/0.5 mg estradiol (E2) and Angeliq 0.5 mg DRSP/1 mg E2 are both used after menopause to reduce moderate to severe hot flashes.oEstrogens are hormones made by womans ovaries. The ovaries normally stop making estrogens when woman is between 45 to 55 years 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.oWhen the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (hot flashes or hot flushes). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Angeliq.oAngeliq 0.5 mg drospirenone (DRSP)/1 mg estradiol (E2) is used after menopause to treat moderate to severe dryness, itching, and burning in or around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Angeliq to control these problems. If you use Angeliq only to treat dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether topical vaginal product would be better for you.Who should not take Angeliq Do not start taking Angeliq if you:ohave had your uterus removed (hysterectomy). oAngeliq contains progestin to decrease the chances of getting cancer of the uterus. If you do not have uterus, you do not need progestin and you should not use Angeliq.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.ocurrently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take Angeliq.ohad stroke or heart attack in the past year.ocurrently have or have had blood clots.ohave kidney disease, liver disease, or disease of your adrenal glands. Angeliq contains drospirenone which may increase the potassium level in your blood. Liver, kidney, or adrenal gland disease may also increase the potassium level in your blood.ohave been diagnosed with bleeding disorder.oare allergic to Angeliq or any of its ingredients. See the end of this leaflet for list of ingredients in Angeliq.oare pregnant or plan to become pregnant.What should tell my healthcare provider before taking Angeliq Before you take Angeliq, tell your healthcare provider if you:ohave or have had problems with your adrenal glands. ohave high levels of fat in your blood (triglycerides)ohave any other medical conditions. Your healthcare provider may need to check you more carefully if you have certain conditions, such as: asthma (wheezing)epilepsy (seizures)migraineendometriosislupushypertension (high blood pressure)problems with your heart, liver, thyroid or kidneysbenign breast diseasehave high calcium in your bloodhave high potassium levels in your bloodhave low sodium levels in your bloodoare pregnant or plan to become pregnant. Angeliq is not for pregnant women. If you think you may be pregnant, you should have pregnancy test and know the results before you start taking Angeliq.oare breastfeeding or planning to breastfeed. You should not breastfeed while taking Angeliq. The hormone in Angeliq can decrease the amount of breast milk you make. Also, the hormone in Angeliq can pass into your milk. Talk to your healthcare provider about the best way to feed your baby if you take Angeliq.Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Angeliq works. Some other medicines and food products may increase or decrease the concentrations of the hormones in Angeliq in the blood. Angeliq may also affect how your other medicines work. Angeliq may increase the potassium level in your blood and some medicines may also increase potassium level. In some situations, your healthcare provider may recommend testing your blood for potassium level.Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.If you are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop taking Angeliq.How should take AngeliqoTake one Angeliq tablet at the same time each day.oTake Angeliq tablets whole. Do not break, crush, dissolve, or chew Angeliq tablets before swallowing. If you cannot swallow Angeliq tablets whole, tell your healthcare provider. You may need different medicine.oIf you miss dose of Angeliq, take it as soon as possible.oIf more than 24 hours have passed since you missed dose of Angeliq, you should not take the missed dose. oEstrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about whether you still need treatment with Angeliq. What are the possible side effects of AngeliqAngeliq may cause serious side effects. Serious but less common side effects include:oHeart attack oStroke oBlood clots oDementia oBreast cancer oCancer of the lining of the uterus (womb) oCancer of the ovary oHigh blood pressure oHigh blood sugaroGallbladder diseaseoLiver problemsoEnlargement of benign tumors of the uterus (fibroids)Call your healthcare provider right away if you have any of the following warning signs or any other unusual symptoms that concern you: oNew breast lumps 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 Less serious, but common side effects include:oHeadache oBreast painoIrregular vaginal bleeding or spotting oStomach or abdominal pain oNausea oDiarrheaoVaginal yeast infectionoFluid RetentionoMoodinessTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of Angeliq. For more information, ask your healthcare provider or pharmacist about side effects.You may report side effects to Bayer HealthCare Pharmaceuticals at 1-888-842-2937 or to FDA at 1-800-FDA-1088. How should store Angeliq Store Angeliq at room temperature between 59F to 86F (15C to 30C).Keep Angeliq and all medicines out of the reach of children. What can do to lower my chances of serious side effect with AngeliqoTalk with your healthcare provider regularly about whether you should continue taking Angeliq. oSee your healthcare provider right away if you get vaginal bleeding while taking Angeliq. oHave pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, 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. Ask your healthcare provider for ways to lower your chances for getting heart disease. General information about the safe and effective use of Angeliq.Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Angeliq for conditions for which it was not prescribed. Do not give Angeliq to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about Angeliq. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Angeliq that is written for health professionals. For more information, go to www.angeliq-us.com by or calling our toll free number (1-888-842-2937).What are the ingredients in AngeliqActive ingredients: drospirenone (a progestin) and estradiol. Inactive ingredients 0.5 mg DRSP/1 mg E2 tablets: lactose monohydrate NF, corn starch NF, pregelatinized starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, and ferric oxide pigment NF. Inactive ingredients in 0.25 mg DRSP/0.5 mg E2 tablets: lactose monohydrate NF, corn starch NF, pregelatinized starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, and yellow ferric oxide pigment NF.This Patient Information has been approved by the U.S. Food and Drug Administration.Manufactured for:Bayer HealthCare Pharmaceuticals Inc.Whippany, NJ 07981(C)2015 Bayer HealthCare Pharmaceuticals Inc.All rights reserved.June 2015Bayer HealthCare Pharmaceuticals Inc.. oAngeliq 0.25 mg drospirenone (DRSP)/0.5 mg estradiol (E2) and Angeliq 0.5 mg DRSP/1 mg E2 are both used after menopause to reduce moderate to severe hot flashes.. oEstrogens are hormones made by womans ovaries. The ovaries normally stop making estrogens when woman is between 45 to 55 years 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.. oWhen the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (hot flashes or hot flushes). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Angeliq.. oAngeliq 0.5 mg drospirenone (DRSP)/1 mg estradiol (E2) is used after menopause to treat moderate to severe dryness, itching, and burning in or around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Angeliq to control these problems. If you use Angeliq only to treat dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether topical vaginal product would be better for you.. ohave had your uterus removed (hysterectomy). oAngeliq contains progestin to decrease the chances of getting cancer of the uterus. If you do not have uterus, you do not need progestin and you should not use Angeliq.. 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.. ocurrently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take Angeliq.. ohad stroke or heart attack in the past year.. ocurrently have or have had blood clots.. ohave kidney disease, liver disease, or disease of your adrenal glands. Angeliq contains drospirenone which may increase the potassium level in your blood. Liver, kidney, or adrenal gland disease may also increase the potassium level in your blood.. ohave been diagnosed with bleeding disorder.. oare allergic to Angeliq or any of its ingredients. See the end of this leaflet for list of ingredients in Angeliq.. oare pregnant or plan to become pregnant.. ohave or have had problems with your adrenal glands. ohave high levels of fat in your blood (triglycerides). ohave any other medical conditions. Your healthcare provider may need to check you more carefully if you have certain conditions, such as: asthma (wheezing)epilepsy (seizures)migraineendometriosislupushypertension (high blood pressure)problems with your heart, liver, thyroid or kidneysbenign breast diseasehave high calcium in your bloodhave high potassium levels in your bloodhave low sodium levels in your blood. asthma (wheezing). epilepsy (seizures). migraine. endometriosis. lupus. hypertension (high blood pressure). problems with your heart, liver, thyroid or kidneys. benign breast disease. have high calcium in your blood. have high potassium levels in your blood. have low sodium levels in your blood. oare pregnant or plan to become pregnant. Angeliq is not for pregnant women. If you think you may be pregnant, you should have pregnancy test and know the results before you start taking Angeliq.. oare breastfeeding or planning to breastfeed. You should not breastfeed while taking Angeliq. The hormone in Angeliq can decrease the amount of breast milk you make. Also, the hormone in Angeliq can pass into your milk. Talk to your healthcare provider about the best way to feed your baby if you take Angeliq.. oTake one Angeliq tablet at the same time each day.. oTake Angeliq tablets whole. Do not break, crush, dissolve, or chew Angeliq tablets before swallowing. If you cannot swallow Angeliq tablets whole, tell your healthcare provider. You may need different medicine.. oIf you miss dose of Angeliq, take it as soon as possible.. oIf more than 24 hours have passed since you missed dose of Angeliq, you should not take the missed dose. oEstrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about whether you still need treatment with Angeliq. oHeart attack oStroke oBlood clots oDementia oBreast cancer oCancer of the lining of the uterus (womb) oCancer of the ovary oHigh blood pressure oHigh blood sugar. oGallbladder disease. oLiver problems. oEnlargement of benign tumors of the uterus (fibroids). oNew breast lumps 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 oHeadache oBreast pain. oIrregular vaginal bleeding or spotting oStomach or abdominal pain oNausea oDiarrhea. oVaginal yeast infection. oFluid Retention. oMoodiness. oTalk with your healthcare provider regularly about whether you should continue taking Angeliq. oSee your healthcare provider right away if you get vaginal bleeding while taking Angeliq. oHave pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, 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. Ask your healthcare provider for ways to lower your chances for getting heart disease.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oDo not use with conditions that predispose to hyperkalemia (5.2)oEstrogens increase the risk of gallbladder disease (5.5)oDiscontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.6, 5.7, 5.9, 5.10)oMonitor thyroid function in women on thyroid replacement therapy (5.11, 5.19). oDo not use with conditions that predispose to hyperkalemia (5.2). oEstrogens increase the risk of gallbladder disease (5.5). oDiscontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.6, 5.7, 5.9, 5.10). oMonitor thyroid function in women on thyroid replacement therapy (5.11, 5.19). 5.1 Cardiovascular Disorders. An increased risk of PE, DVT, stroke and MI have been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT have 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/or obesity) and/or venous thromboembolism (VTE) [for example, personal history or family history of VTE, obesity, systemic lupus erythematosus] should be managed appropriately.. Stroke In the Womens Health Initiative (WHI) estrogen plus progestin substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women years) [see Clinical Studies (14.4)]. The increase in risk was demonstrated after the first year and persisted.1 Should stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.In the WHI estrogen-alone substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted [see Clinical Studies (14.4)]. Should stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1 Coronary Heart Disease. In the WHI estrogen plus progestin substudy, there was 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 trend toward decreasing relative risk was reported in years through [see Clinical Studies (14.4)].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 (14.4)].Subgroup analyses of women 50 to 59 years of age suggest statistically non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in women with less than 10 years since menopause (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 and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism In the WHI estrogen plus progestin substudy, statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted3 [see Clinical Studies (14.4)]. Should VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first years4 [see Clinical Studies (14.4)]. Should VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least to weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 5.2 Hyperkalemia. Angeliq contains the progestin DRSP that has antialdosterone activity, including the potential for hyperkalemia in high-risk patients. Angeliq is contraindicated in patients with conditions that predispose to hyperkalemia (renal impairment, hepatic impairment, and adrenal insufficiency).Use caution when prescribing Angeliq to women who regularly take other medications that can increase potassium, such as non-steroidal anti-inflammatory drugs (NSAIDs), potassium-sparing diuretics, potassium supplements, angiotensin converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, heparin and aldosterone antagonists. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (for example, ketoconazole, itraconazole, voriconazole), human immunodeficiency virus (HIV)/hepatitis virus (HCV) protease inhibitors (for example, indinavir, boceprevir), and clarithromycin [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 5.3 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 mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of 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. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09 and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups5 [see Clinical Studies (14.4)]. 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 (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk [see Clinical Studies (14.4)]. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not 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 has been reported to result in an increase in abnormal mammograms requiring further evaluation. 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 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 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for to 10 years or more. This risk has been shown to persist for at least to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer.. Ovarian Cancer The WHI estrogen plus progestin substudy reported statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was versus cases per 10,000 women-years.7 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% confidence interval [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 to 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.. 5.4 Probable Dementia. In the Womens Health Initiative 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 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-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.5)].In the WHIMS estrogen-alone ancillary study of WHI, population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). 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 (14.5)]. 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 1.19-2.60). 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 (14.5)].. 5.5 Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 5.6 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 concentration.. 5.7 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 sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.. 5.8 Elevated Blood Pressure In small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogen therapy on blood pressure was not seen. 5.9 Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.. 5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with impaired liver function. For women with history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. The clearance of drospirenone was decreased in patients with moderate hepatic impairment. 5.11 Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) concentrations. 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 estrogens 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 concentrations in an acceptable range. 5.12 Fluid Retention Estrogens and 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 are prescribed. 5.13 Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 5.14 Hyponatremia As an aldosterone antagonist, drospirenone may increase the possibility of hyponatremia in high-risk patients.. 5.15 Exacerbation of Endometriosis Endometriosis may be exacerbated with administration of estrogens.. 5.16 Hereditary Angioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.. 5.17 Exacerbation of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus otosclerosis, chorea minor and hepatic hemangiomas and should be used with caution in women with these conditions. In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.. 5.18 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol concentrations have not been shown to be useful in the management of moderate to severe vasomotor symptoms. 5.19 Interference with Laboratory Tests 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, II-VII-X complex, and beta-thromboglobulin; decreased concentrations of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased concentrations of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased TBG concentrations leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 concentrations (by column or by radioimmunoassay) or T3 concentrations 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, 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/renin substrate, alpha-l-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride concentrations. Impaired glucose tolerance. Reduced response to metyrapone test.