Prempro

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] • Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] In two prospective, randomized clinical studies, the most common adverse reactions > 5 percent are abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, and leukorrhea. ( 6.1 )To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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 trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a 1-year clinical trial that included 678 postmenopausal women treated with PREMPRO and 351 postmenopausal women treated with PREMPHASE, the following adverse reactions occurred at a rate ≥ 1 percent, see Table 1 . TABLE 1: ALL TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT Body System PREMPRO 0.625 mg/2.5 mg continuous PREMPRO 0.625 mg/5 mg continuous PREMPHASE 0.625 mg/5 mg sequential Adverse event (n = 340) (n = 338) (n = 351) Body As A Whole Abdominal pain 35 (10%) 51 (15%) 58 (17%) Asthenia 13 (4%) 18 (5%) 21 (6%) Back pain 19 (6%) 16 (5%) 23 (7%) Chest pain 5 (1%) 4 (1%) 4 (1%) Flu syndrome 1 (<1%) 1 (<1%) 4 (1%) Generalized edema 12 (4%) 12 (4%) 8 (2%) Headache 64 (19%) 52 (15%) 66 (19%) Infection 2 (<1%) 4 (1)% 0 Moniliasis 4 (1%) 3 (<1%) 4 (1%) Pain 12 (4%) 14 (4%) 15 (4%) Pelvic pain 11 (3%) 13 (4%) 16 (5%) Cardiovascular System Hypertension 7 (2%) 7 (2%) 6 (2%) Migraine 6 (2%) 8 (2%) 7 (2%) Palpitation 2 (<1%) 3 (<1%) 4 (1%) Vasodilatation 2 (<1%) 7 (2%) 2 (<1%) Digestive System Diarrhea 4 (1%) 3 (<1%) 7 (2%) Dyspepsia 5 (1%) 5 (1%) 7 (2%) Eructation 0 2 (<1%) 4 (1%) Flatulence 25 (7%) 27 (8%) 24 (7%) Increased appetite 1 (<1%) 5 (1%) 5 (1%) Nausea 26 (8%) 19 (6%) 26 (7%) Metabolic and Nutritional Edema 5 (1%) 6 (2%) 3 (<1%) Glucose tolerance decreased 2 (<1%) 5 (1%) 4 (1%) Peripheral edema 11 (3%) 10 (3%) 11 (3%) Weight gain 9 (3%) 10 (3%) 11 (3%) Musculoskeletal System Arthralgia 6 (2%) 2 (<1%) 7 (2%) Leg cramps 8 (2%) 11 (3%) 12 (3%) Nervous System Depression 14 (4%) 26 (8%) 29 (8%) Dizziness 9 (3%) 8 (2%) 7 (2%) Emotional lability 5 (1%) 5 (1%) 6 (2%) Hypertonia 4 (1%) 4 (1%) 7 (2%) Insomnia 7 (2%) 6 (2%) 4 (1%) Nervousness 4 (1%) 9 (3%) 6 (2%) Skin and Appendages Acne 1 (<1%) 5 (1%) 4 (1%) Alopecia 3 (<1%) 4 (1%) 0 Dry skin 2 (<1%) 3 (<1%) 4 (1%) Pruritus 20 (6%) 18 (5%) 13 (4%) Rash 8 (2%) 6 (2%) 7 (2%) Sweating 2 (<1%) 4 (1%) 2 (<1%) Urogenital System Breast engorgement 5 (1%) 5 (1%) 0 Breast enlargement 14 (4%) 14 (4%) 14 (4%) Breast neoplasm 2 (<1%) 2 (<1%) 4 (1%) Breast pain 110 (32%) 123 (36%) 109 (31%) Cervix disorder 10 (3%) 6 (2%) 10 (3%) Dysmenorrhea 26 (8%) 18 (5%) 44 (13%) Leukorrhea 19 (6%) 13 (4%) 29 (8%) Menstrual disorder 7 (2%) 1 (<1%) 5 (1%) Menorrhagia 0 1 (<1%) 5 (1%) Metrorrhagia 13 (4%) 5 (1%) 7 (1%) Papanicolaou smear suspicious 5 (1%) 0 8 (2%) Urinary incontinence 4 (1%) 2 (<1%) 1 (<1%) Uterine spasm 7 (2%) 4 (1%) 7 (2%) Vaginal hemorrhage 5 (1%) 3 (<1%) 8 (2%) Vaginal moniliasis 5 (1%) 6 (2%) 7 (2%) Vaginitis 13 (4%) 13 (4%) 10 (3%) In addition, phargyngitis and sinusitis were reported as two of the more frequent adverse events (>5 percent) in the PREMPRO clinical study. For pharyngitis, of the 121 events, six events were considered by the investigator causally related to study drug. For sinusitis, of the 73 events, one event was considered as casually related to study drug. During the first year of a 2-year clinical trial with postmenopausal women between 40 and 65 years of age (88 percent Caucasian), 989 postmenopausal women received continuous regimens of PREMPRO, and 332 received placebo tablets. Table 2 summarizes adverse reactions that occurred at a rate ≥ 1 percent in at least 1 treatment group. TABLE 2: ALL TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY OF ≥ 1 PERCENT Body System Adverse event PREMPRO 0.625/2.5 continuous (N=331) PREMPRO 0.45/1.5 continuous (N=331) PREMPRO 0.3/1.5 continuous (N=327) PLACEBO daily (N=332) Any adverse event 214 (65) 208 (63) 188 (57) 164 (49) Body as a Whole Abdominal pain 38 (11) 33 (10) 24 (7) 21 (6) Asthenia 11 (3) 11 (3) 12 (4) 3 (1) Back pain 12 (4) 12 (4) 8 (2) 4 (1) Chest pain 4 (1) 2 (1) 1 (0) 2 (1) Generalized edema 7 (2) 5 (2) 6 (2) 8 (2) Headache 45 (14) 45 (14) 57 (17) 46 (14) Moniliasis 3 (1) 6 (2) 4 (1) 1 (0) Pain 9 (3) 10 (3) 17 (5) 14 (4) Pelvic pain 9 (3) 7 (2) 5 (2) 4 (1) Cardiovascular System Hypertension 2 (1) 3 (1) 1 (0) 5 (2) Migraine 11 (3) 8 (2) 5 (2) 3 (1) Palpitation 1 (0) 1 (0) 2 (1) 4 (1) Vasodilatation 0 3 (1) 1 (0) 5 (2) Digestive System Constipation 5 (2) 7 (2) 6 (2) 3 (1) Diarrhea 5 (2) 2 (1) 6 (2) 8 (2) Dyspepsia 10 (3) 9 (3) 6 (2) 14 (4) Flatulence 16 (5) 18 (5) 13 (4) 8 (2) Increased appetite 6 (2) 2 (1) 0 2 (1) Nausea 13 (4) 13 (4) 16 (5) 16 (5) Metabolic and nutritional Peripheral edema 7 (2) 8 (2) 4 (1) 3 (1) Weight gain 9 (3) 8 (2) 6 (2) 14 (4) Musculoskeletal System Arthralgia 2 (1) 3 (1) 3 (1) 5 (2) Leg cramps 13 (4) 7 (2) 10 (3) 4 (1) Nervous System Anxiety 5 (2) 4 (1) 1 (0) 4 (1) Depression 23 (7) 11 (3) 11 (3) 17 (5) Dizziness 3 (1) 8 (2) 6 (2) 5 (2) Emotional lability 10 (3) 10 (3) 9 (3) 8 (2) Insomnia 8 (2) 7 (2) 9 (3) 14 (4) Nervousness 6 (2) 3 (1) 4 (1) 6 (2) Skin and Appendages Acne 7 (2) 3 (1) 0 3 (1) Alopecia 1 (0) 6 (2) 4 (1) 2 (1) Pruritus 8 (2) 10 (3) 9 (3) 3 (1) Rash 0 6 (2) 4 (1) 2 (1) Skin discoloration 5 (2) 1 (0) 3 (1) 1 (0) Sweating 3 (1) 1 (0) 0 4 (1) Urogenital System Breast disorder 7 (2) 6 (2) 5 (2) 6 (2) Breast enlargement 18 (5) 9 (3) 5 (2) 3 (1) Breast neoplasm 8 (2) 7 (2) 5 (2) 7 (2) Breast pain 87 (26) 66 (20) 41 (13) 26 (8) Cervix disorder 7 (2) 2 (1) 2 (1) 0 Dysmenorrhea 14 (4) 18 (5) 9 (3) 2 (1) Hematuria 4 (1) 3 (1) 1 (0) 2 (1) Leukorrhea 7 (2) 14 (4) 9 (3) 6 (2) Metrorrhagia 7 (2) 14 (4) 4 (1) 1 (0) Urinary tract infection 0 1 (0) 1 (0) 4 (1) Uterine spasm 13 (4) 11 (3) 7 (2) 2 (1) Vaginal dryness 2 (1) 1 (0) 0 6 (2) Vaginal hemorrhage 18 (5) 14 (4) 7 (2) 0 Vaginal moniliasis 13 (4) 11 (3) 8 (2) 5 (2) Vaginitis 6 (2) 8 (2) 7 (2) 1 (0) In addition, the following events were considered as related to the study drug with an incidence less than 1 percent, including accidental injury, infection, myalgia, cough increased, rhinitis, sinusitis, and upper respiratory infection. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PREMPRO or PREMPHASE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Abnormal uterine bleeding, dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata, vaginitis, vaginal candidiasis, amenorrhea, changes in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer. Breasts Tenderness, enlargement, pain, nipple discharge, galactorrhea, fibrocystic breast changes, breast cancer. Cardiovascular Deep and superficial venous thrombosis, pulmonary embolism, superficial thrombophlebitis, myocardial infarction, stroke, increase in blood pressure. Gastrointestinal Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, changes in appetite, ischemic colitis. Skin Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, urticaria, rash, acne. Eyes Retinal vascular thrombosis, intolerance of contact lenses. Central Nervous System Headache, migraine, dizziness, mental depression, exacerbation of chorea, mood disturbances, anxiety, irritability, exacerbation of epilepsy, dementia, growth potentiation of benign meningioma. Miscellaneous Increase or decrease in weight, arthralgia, glucose intolerance, edema, changes in libido, exacerbation of asthma, increased triglycerides, hypersensitivity. Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

4 CONTRAINDICATIONS PREMPRO or PREMPHASE therapy should not be used in women with any of the following conditions: • Undiagnosed abnormal genital bleeding • Known, suspected, or history of breast cancer • Known or suspected estrogen-dependent neoplasia • Active DVT, PE, or a history of these conditions • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions • Known anaphylactic reaction or angioedema to PREMPRO/PREMPHASE • Known liver dysfunction or disease • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders • Known or suspected pregnancy • Undiagnosed abnormal genital bleeding ( 4 ) • Known, suspected, or history of breast cancer ( 4 , 5.2 ) • Known or suspected estrogen-dependent neoplasia ( 4 , 5.2 ) • Active DVT, PE, or a history of these conditions ( 4 , 5.1 ) • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.1 ) • Known anaphylactic reaction or angioedema to PREMPRO/PREMPHASE ( 5.15 , 5.16 ) • Known liver dysfunction or disease ( 4 , 5.10 ) • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) • Known or suspected pregnancy ( 4 , 8.1 )

11 DESCRIPTION Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol and 17 β-dihydroequilin. Medroxyprogesterone acetate is a derivative of progesterone. It is a white to off-white, odorless, crystalline powder, stable in air, melting between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water. The chemical name for MPA is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. Its molecular formula is C 24 H 34 O 4 , with a molecular weight of 386.53. Its structural formula is: PREMPRO 0.3 mg/1.5 mg and 0.45 mg/1.5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, microcrystalline cellulose, carnauba wax, hypromellose, hydroxypropyl cellulose, sucrose, Eudragit NE 30D, lactose monohydrate, magnesium stearate, polyethylene glycol, titanium dioxide, yellow iron oxide, propylene glycol and black iron oxide. PREMPRO 0.625 mg/2.5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, microcrystalline cellulose, carnauba wax, hypromellose, hydroxypropyl cellulose, sucrose, Eudragit NE 30D, lactose monohydrate, magnesium stearate, polyethylene glycol, propylene glycol, titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide. PREMPRO 0.625 mg/5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, carnauba wax, Eudragit NE 30D, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, titanium dioxide, triethyl citrate, FD&C Blue No. 2, black iron oxide, and propylene glycol. PREMPHASE Each maroon Premarin tablets for oral administration contain 0.625 mg of conjugated estrogens and the following inactive ingredients: calcium phosphate tribasic, carnauba wax, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, titanium dioxide, propylene glycol, FD&C Blue No. 2, and FD&C Red No. 40. These tablets comply with USP Dissolution Test 5. Each light-blue tablet for oral administration contains 0.625 mg of conjugated estrogens, 5 mg of medroxyprogesterone acetate, and the following inactive ingredients: calcium phosphate tribasic, carnauba wax, Eudragit NE 30D, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, titanium dioxide, triethyl citrate, FD&C Blue No. 2, black iron oxide, and propylene glycol. PREMPRO Tablet Strength Tablet Color Contains 0.3 mg/1.5 mg Yellow iron oxide and black iron oxide 0.45 mg/1.5 mg Yellow iron oxide and black iron oxide 0.625 mg/2.5 mg Red iron oxide, yellow iron oxide, and black iron oxide 0.625 mg/5 mg FD&C Blue No. 2 and black iron oxide PREMPHASE Tablet Strength Tablet Color Contains 0.625 mg FD&C Blue No. 2 and FD&C Red No. 40 0.625 mg/5 mg FD&C Blue No. 2 and black iron oxide Chemical Structure

2 DOSAGE AND ADMINISTRATION Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. PREMPRO: one tablet containing conjugated estrogens (CE) plus medroxyprogesterone acetate (MPA) taken orally once daily. ( 2 ) PREMPHASE: one maroon tablet containing 0.625 mg CE taken orally on days 1 through 14, and one light-blue tablet containing 0.625 mg CE plus 5.0 mg MPA taken orally on days 15 through 28. ( 2 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause PREMPRO therapy consists of a single tablet to be taken orally once daily. PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg Premarin [conjugated estrogens (CE)] tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg of medroxyprogesterone acetate (MPA) taken on days 15 through 28. 2.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause PREMPRO therapy consists of a single tablet to be taken orally once daily. PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg CE tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg MPA taken on days 15 through 28. When prescribing solely for the treatment of moderate to severe vulvar and vaginal atrophy, topical vaginal products should be considered. 2.3 Prevention of Postmenopausal Osteoporosis PREMPRO therapy consists of a single tablet to be taken orally once daily. PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg CE tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg of MPA taken on days 15 through 28. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.

1 INDICATIONS AND USAGE PREMPRO/PREMPHASE is an estrogen plus progestin indicated in a woman with a uterus for: • Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) • Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) • Prevention of Postmenopausal Osteoporosis ( 1.3 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause 1.3 Prevention of Postmenopausal Osteoporosis

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

7 DRUG INTERACTIONS Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with CE plus MPA. • Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism ( 7.1 ) • Aminoglutethimide administered concomitantly with MPA may significantly depress the bioavailability of medroxyprogesterone acetate ( 7.1 ) 7.1 Metabolic Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects. Aminoglutethimide administered concomitantly with MPA may significantly depress the bioavailability of MPA.

5.19 Drug-Laboratory Test Interactions Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay), or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL 2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels. Impaired glucose tolerance.

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 a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women. Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation; although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue. Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity. 12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for PREMPRO or PREMPHASE tablets. 12.3 Pharmacokinetics Absorption PREMPRO and PREMPHASE contain a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. MPA is well absorbed from the gastrointestinal tract. Table 3 and Table 4 summarize the mean pharmacokinetic parameters for select unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of PREMPRO to healthy, postmenopausal women. TABLE 3: PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA) DRUG 2 × 0.625 mg CE/2.5 mg MPA Combination Tablets (n = 54) 2 × 0.625 mg CE/5 mg MPA Combination Tablets (n = 51) BA* = Baseline adjusted C max = peak plasma concentration t max = time peak concentration occurs t 1/2 = apparent terminal-phase disposition half-life (0.693/λ z ) AUC = total area under the concentration-time curve PK Parameter Arithmetic Mean (%CV) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) Unconjugated Estrogens Estrone 175 (23) 7.6 (24) 31.6 (23) 5358 (34) 124 (43) 10 (35) 62.2 (137) 6303 (40) BA* -Estrone 159 (26) 7.6 (24) 16.9 (34) 3313 (40) 104 (49) 10 (35) 26.0 (100) 3136 (51) Equilin 71 (31) 5.8 (34) 9.9 (35) 951 (43) 54 (43) 8.9 (34) 15.5 (53) 1179 (56) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Conjugated Estrogens Total Estrone 6.6 (38) 6.1 (28) 20.7 (34) 116 (59) 6.3 (48) 9.1 (29) 23.6 (36) 151 (42) BA* -Total Estrone 6.4 (39) 6.1 (28) 15.4 (34) 100 (57) 6.2 (48) 9.1 (29) 20.6 (35) 139 (40) Total Equilin 5.1 (45) 4.6 (35) 11.4 (25) 50 (70) 4.2 (52) 7.0 (36) 17.2 (131) 72 (50) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Medroxyprogesterone Acetate MPA 1.5 (40) 2.8 (54) 37.6 (30) 37 (30) 4.8 (31) 2.4 (50) 46.3 (39) 102 (28) TABLE 4. PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA) DRUG 4 × 0.45 mg CE/1.5 mg MPA Combination (n = 65) BA* = Baseline adjusted C max = peak plasma concentration t max = time peak concentration occurs t 1/2 = apparent terminal-phase disposition half-life (0.693/λ z ) AUC = total area under the concentration-time curve PK Parameter Arithmetic Mean (%CV) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) Unconjugated Estrogens Estrone 149 (35) 8.9 (35) 37.5 (35) 6641 (39) BA* -Estrone 130 (40) 8.9 (35) 21.2 (35) 3799 (47) Equilin 83 (38) 8.3 (48) 15.9 (44) 1889 (40) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Conjugated Estrogens Total Estrone 5.4 (49) 7.9 (48) 22.4 (53) 119 (48) BA* -Total Estrone 5.2 (48) 7.9 (48) 15.1 (29) 100 (47) Total Equilin 4.3 (42) 6.5 (45) 11.6 (31) 74 (48) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Medroxyprogesterone Acetate MPA 0.7 (66) 2.0 (52) 26.2 (35) 5.0 (61) Food-Effect: Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when PREMPRO or PREMPHASE is administered with a high-fat breakfast. Administration with food decreased the C max of total estrone by 18 to 34 percent and increased total equilin C max by 38 percent compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA C max and increases MPA AUC by approximately 20 to 30 percent. Dose Proportionality: The C max and AUC values for MPA observed in two separate pharmacokinetic studies conducted with 2 PREMPRO 0.625 mg/2.5 mg or 2 PREMPRO or PREMPHASE 0.625 mg/5 mg tablets exhibited nonlinear dose proportionality; doubling the MPA dose from 2 × 2.5 to 2 × 5 mg increased the mean C max and AUC by 3.2- and 2.8-fold, respectively. The dose proportionality of estrogens and medroxyprogesterone acetate was assessed by combining pharmacokinetic data across another two studies totaling 61 healthy, postmenopausal women. Single conjugated estrogens doses of 2 × 0.3 mg, 2 × 0.45 mg, or 2 × 0.625 mg were administered either alone or in combination with medroxyprogesterone acetate doses of 2 × 1.5 mg or 2 × 2.5 mg. Most of the estrogen components demonstrated dose proportionality; however, several estrogen components did not. Medroxyprogesterone acetate pharmacokinetic parameters increased in a dose-proportional manner. Distribution 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. Estrogens circulate in the blood largely bound to SHBG and albumin. MPA is approximately 90 percent bound to plasma proteins, but does not bind to SHBG. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates, with only minor amounts excreted as sulfates. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women. Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation; although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue. Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity.

12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for PREMPRO or PREMPHASE tablets.

12.3 Pharmacokinetics Absorption PREMPRO and PREMPHASE contain a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. MPA is well absorbed from the gastrointestinal tract. Table 3 and Table 4 summarize the mean pharmacokinetic parameters for select unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of PREMPRO to healthy, postmenopausal women. TABLE 3: PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA) DRUG 2 × 0.625 mg CE/2.5 mg MPA Combination Tablets (n = 54) 2 × 0.625 mg CE/5 mg MPA Combination Tablets (n = 51) BA* = Baseline adjusted C max = peak plasma concentration t max = time peak concentration occurs t 1/2 = apparent terminal-phase disposition half-life (0.693/λ z ) AUC = total area under the concentration-time curve PK Parameter Arithmetic Mean (%CV) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) Unconjugated Estrogens Estrone 175 (23) 7.6 (24) 31.6 (23) 5358 (34) 124 (43) 10 (35) 62.2 (137) 6303 (40) BA* -Estrone 159 (26) 7.6 (24) 16.9 (34) 3313 (40) 104 (49) 10 (35) 26.0 (100) 3136 (51) Equilin 71 (31) 5.8 (34) 9.9 (35) 951 (43) 54 (43) 8.9 (34) 15.5 (53) 1179 (56) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Conjugated Estrogens Total Estrone 6.6 (38) 6.1 (28) 20.7 (34) 116 (59) 6.3 (48) 9.1 (29) 23.6 (36) 151 (42) BA* -Total Estrone 6.4 (39) 6.1 (28) 15.4 (34) 100 (57) 6.2 (48) 9.1 (29) 20.6 (35) 139 (40) Total Equilin 5.1 (45) 4.6 (35) 11.4 (25) 50 (70) 4.2 (52) 7.0 (36) 17.2 (131) 72 (50) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Medroxyprogesterone Acetate MPA 1.5 (40) 2.8 (54) 37.6 (30) 37 (30) 4.8 (31) 2.4 (50) 46.3 (39) 102 (28) TABLE 4. PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA) DRUG 4 × 0.45 mg CE/1.5 mg MPA Combination (n = 65) BA* = Baseline adjusted C max = peak plasma concentration t max = time peak concentration occurs t 1/2 = apparent terminal-phase disposition half-life (0.693/λ z ) AUC = total area under the concentration-time curve PK Parameter Arithmetic Mean (%CV) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) Unconjugated Estrogens Estrone 149 (35) 8.9 (35) 37.5 (35) 6641 (39) BA* -Estrone 130 (40) 8.9 (35) 21.2 (35) 3799 (47) Equilin 83 (38) 8.3 (48) 15.9 (44) 1889 (40) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Conjugated Estrogens Total Estrone 5.4 (49) 7.9 (48) 22.4 (53) 119 (48) BA* -Total Estrone 5.2 (48) 7.9 (48) 15.1 (29) 100 (47) Total Equilin 4.3 (42) 6.5 (45) 11.6 (31) 74 (48) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Medroxyprogesterone Acetate MPA 0.7 (66) 2.0 (52) 26.2 (35) 5.0 (61) Food-Effect: Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when PREMPRO or PREMPHASE is administered with a high-fat breakfast. Administration with food decreased the C max of total estrone by 18 to 34 percent and increased total equilin C max by 38 percent compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA C max and increases MPA AUC by approximately 20 to 30 percent. Dose Proportionality: The C max and AUC values for MPA observed in two separate pharmacokinetic studies conducted with 2 PREMPRO 0.625 mg/2.5 mg or 2 PREMPRO or PREMPHASE 0.625 mg/5 mg tablets exhibited nonlinear dose proportionality; doubling the MPA dose from 2 × 2.5 to 2 × 5 mg increased the mean C max and AUC by 3.2- and 2.8-fold, respectively. The dose proportionality of estrogens and medroxyprogesterone acetate was assessed by combining pharmacokinetic data across another two studies totaling 61 healthy, postmenopausal women. Single conjugated estrogens doses of 2 × 0.3 mg, 2 × 0.45 mg, or 2 × 0.625 mg were administered either alone or in combination with medroxyprogesterone acetate doses of 2 × 1.5 mg or 2 × 2.5 mg. Most of the estrogen components demonstrated dose proportionality; however, several estrogen components did not. Medroxyprogesterone acetate pharmacokinetic parameters increased in a dose-proportional manner. Distribution 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. Estrogens circulate in the blood largely bound to SHBG and albumin. MPA is approximately 90 percent bound to plasma proteins, but does not bind to SHBG. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates, with only minor amounts excreted as sulfates. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

20231029

33

3 DOSAGE FORMS AND STRENGTHS PREMPRO (conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.3 mg CE plus 1.5 mg MPA oval / cream PREMPRO 0.3/1.5 0.45 mg CE plus 1.5 mg MPA oval / gold PREMPRO 0.45/1.5 0.625 mg CE plus 2.5 mg MPA oval / peach PREMPRO 0.625/2.5 0.625 mg CE plus 5 mg MPA oval / light blue PREMPRO 0.625/5 PREMPHASE (conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.625 mg CE oval / maroon (14 tablets) PREMARIN 0.625 0.625 mg CE plus 5 mg MPA oval / light-blue (14 tablets) PREMPRO 0.625/5 PREMPRO Tablets: 0.3 mg CE plus 1.5 mg MPA, 0.45 mg CE plus 1.5 mg MPA, 0.625 mg CE plus 2.5 mg MPA, 0.625 mg CE plus 5 mg MPA. PREMPHASE Tablets: 0.625 mg CE, 0.625 mg CE plus 5 mg MPA.

Premphase conjugated estrogens and medroxyprogesterone acetate Prempro conjugated estrogens and medroxyprogesterone acetate ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE HYDROXYPROPYL CELLULOSE (1600000 WAMW) MICROCRYSTALLINE CELLULOSE LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 400 SUCROSE TITANIUM DIOXIDE FD&C BLUE NO. 2 CARNAUBA WAX TRIBASIC CALCIUM PHOSPHATE FERROSOFERRIC OXIDE HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) METHACRYLIC ACID AND ETHYL ACRYLATE COPOLYMER TRIETHYL CITRATE PROPYLENE GLYCOL LIGHT BLUE OVAL PREMPRO;0625;5 Premarin conjugated estrogens ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED HYDROXYPROPYL CELLULOSE (1600000 WAMW) MICROCRYSTALLINE CELLULOSE LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 400 SUCROSE TITANIUM DIOXIDE FD&C BLUE NO. 2 FD&C RED NO. 40 TRIBASIC CALCIUM PHOSPHATE POWDERED CELLULOSE HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) CARNAUBA WAX PROPYLENE GLYCOL MAROON OVAL PREMARIN;0625 Prempro conjugated estrogens and medroxyprogesterone acetate ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) SUCROSE LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 400 TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE TRIBASIC CALCIUM PHOSPHATE METHACRYLIC ACID AND ETHYL ACRYLATE COPOLYMER HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) CARNAUBA WAX PROPYLENE GLYCOL CREAM OVAL PREMPRO;03;15 Prempro conjugated estrogens and medroxyprogesterone acetate ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) SUCROSE LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 400 TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE METHACRYLIC ACID AND ETHYL ACRYLATE COPOLYMER TRIBASIC CALCIUM PHOSPHATE HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) CARNAUBA WAX PROPYLENE GLYCOL GOLD OVAL PREMPRO;045;15 Prempro conjugated estrogens and medroxyprogesterone acetate ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) SUCROSE LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 400 TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE METHACRYLIC ACID AND ETHYL ACRYLATE COPOLYMER TRIBASIC CALCIUM PHOSPHATE HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) CARNAUBA WAX PROPYLENE GLYCOL PEACH OVAL PREMPRO;0625;25 Prempro conjugated estrogens and medroxyprogesterone acetate ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) SUCROSE LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 400 CARNAUBA WAX TITANIUM DIOXIDE FD&C BLUE NO. 2 FERROSOFERRIC OXIDE METHACRYLIC ACID AND ETHYL ACRYLATE COPOLYMER TRIBASIC CALCIUM PHOSPHATE HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) PROPYLENE GLYCOL TRIETHYL CITRATE LIGHT BLUE OVAL PREMPRO;0625;5

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breasts, uterus, cervix, vagina, testis, and liver.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breasts, uterus, cervix, vagina, testis, and liver.

NDA020527

Prempro

conjugated estrogens and medroxyprogesterone acetate

0046-1105

HUMAN PRESCRIPTION DRUG

ORAL

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

PRINCIPAL DISPLAY PANEL - 28 Tablet 0.625 mg / 5 mg Blister Pack START HERE Rx only NDC 0046-2575-12 DAY 1 → DAY 2 → DAY 3 → DAY 4 → DAY 5 → DAY 6 → DAY 7 14 maroon tablets of 0.625 mg conjugated estrogens DAY 14 ← DAY 13 ← DAY 12 ← DAY 11 ← DAY 10 ← DAY 9 ← DAY 8 PREMPHASE ® (conjugated estrogens/medroxyprogesterone acetate tablets) DAY 15 → DAY 16 → DAY 17 → DAY 18 → DAY 19 → DAY 20 → DAY 21 14 light-blue tablets of 0.625 mg conjugated estrogens/5 mg medroxyprogesterone acetate DAY 28 ← DAY 27 ← DAY 26 ← DAY 25 ← DAY 24 ← DAY 23 ← DAY 22 Principal Display Panel - 28 Tablet 0.625 mg / 5 mg Blister Pack

This product's label may have been updated. For current package insert and further product information, please visit www.pfizer.com. LAB-0502-9.0 Logo

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling . 17.1 Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2) ] . 17.2 Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . 17.3 Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups of either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization. With PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg, the relief of both the frequency and severity of moderate to severe vasomotor symptoms was shown to be statistically improved compared to placebo at weeks 4 and 12. Table 5 shows the adjusted mean number of hot flushes in the PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, 0.3 mg/1.5 mg, and placebo groups during the initial 12-week period. TABLE 5: SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY – MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS AND THE PLACEBO GROUP – PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LAST OBSERVATION CARRIED FORWARD (LOCF) Treatment Identified by dosage (mg) of Premarin/MPA or placebo. (No. of Patients) -------------------No. of Hot Flushes/Day----------------- Time Period (week) Baseline Mean ± SD Observed Mean ± SD Mean Change ± SD p-Values vs. Placebo There were no statistically significant differences between the 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg groups at any time period. 0.625 mg/2.5 mg (n = 34) 4 11.98 ± 3.54 3.19 ± 3.74 -8.78 ± 4.72 <0.001 12 11.98 ± 3.54 1.16 ± 2.22 -10.82 ± 4.61 <0.001 0.45 mg/1.5 mg (n = 29) 4 12.61 ± 4.29 3.64 ± 3.61 -8.98 ± 4.74 <0.001 12 12.61 ± 4.29 1.69 ± 3.36 -10.92 ± 4.63 <0.001 0.3 mg/1.5 mg (n = 33) 4 11.30 ± 3.13 3.70 ± 3.29 -7.60 ± 4.71 <0.001 12 11.30 ± 3.13 1.31 ± 2.82 -10.00 ± 4.60 <0.001 Placebo (n = 28) 4 11.69 ± 3.87 7.89 ± 5.28 -3.80 ± 4.71 - 12 11.69 ± 3.87 5.71 ± 5.22 -5.98 ± 4.60 - 14.2 Effects on Vulvar and Vaginal Atrophy Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p < 0.001) for all treatment groups. 14.3 Effects on the Endometrium In a 1-year clinical trial of 1,376 women (average age 54 ± 4.6 years) randomized to PREMPRO 0.625 mg/2.5 mg (n = 340), PREMPRO 0.625 mg/5 mg (n = 338), PREMPHASE 0.625 mg/5 mg (n = 351), or Premarin 0.625 mg alone (n = 347), results of evaluable biopsies at 12 months (n = 279, 274, 277, and 283, respectively) showed a reduced risk of endometrial hyperplasia in the two PREMPRO treatment groups (less than 1 percent) and in the PREMPHASE treatment group (less than 1 percent; 1 percent when focal hyperplasia was included) compared to the Premarin group (8 percent; 20 percent when focal hyperplasia was included), see Table 6 . TABLE 6: INCIDENCE OF ENDOMETRIAL HYPERPLASIA AFTER ONE YEAR OF TREATMENT --------------------------Groups------------------------- PREMPRO PREMPRO PREMPHASE Premarin 0.625 mg/2.5 mg 0.625 mg/5 mg 0.625 mg/5 mg 0.625 mg Total number of patients 340 338 351 347 Number of patients with evaluable biopsies 279 274 277 283 No. (%) of patients with biopsies: • All focal and non-focal hyperplasia 2 (<1) Significant (p < 0.001) in comparison with Premarin (0.625 mg) alone. 0 (0) 3 (1) 57 (20) • Excluding focal cystic hyperplasia 2 (<1) 0 (0) 1 (<1) 25 (8) In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 2,001 women (average age 53.3 ± 4.9 years), of whom 88 percent were Caucasian, were treated with either Premarin 0.625 mg alone (n = 348), Premarin 0.45 mg alone (n = 338), Premarin 0.3 mg alone (n = 326) or PREMPRO 0.625 mg/2.5 mg (n = 331), PREMPRO 0.45 mg/1.5 mg (n = 331) or PREMPRO 0.3 mg/1.5 mg (n = 327). Results of evaluable endometrial biopsies at 12 months showed a reduced risk of endometrial hyperplasia or cancer in the PREMPRO treatment groups compared with the corresponding Premarin alone treatment groups, except for the PREMPRO 0.3 mg/1.5 mg and Premarin 0.3 mg alone groups, in each of which there was only 1 case, see Table 7 . No endometrial hyperplasia or cancer was noted in those patients treated with the continuous combined regimens who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study, see Table 8 . TABLE 7: INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCER All cases of hyperplasia/cancer were endometrial hyperplasia, except for 1 patient in the Premarin 0.3 mg group diagnosed with endometrial cancer based on endometrial biopsy and 1 patient in the Premarin/MPA 0.45 mg/1.5 mg group diagnosed with endometrial cancer based on endometrial biopsy. AFTER ONE YEAR OF TREATMENT Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, a third pathologist adjudicated (consensus). -----------------------------------Groups--------------------------------- Patient Prempro 0.625 mg/2.5 mg Premarin 0.625 mg Prempro 0.45 mg/1.5 mg Premarin 0.45 mg Prempro 0.3 mg/1.5 mg Premarin 0.3 mg Total number of patients 331 348 331 338 327 326 Number of patients with evaluable biopsies 278 249 272 279 271 269 No. (%) of patients with biopsies: • Hyperplasia/cancer (consensus For an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least 2 pathologists had to agree on the diagnosis. ) 0 (0) Significant (p < 0.05) in comparison with corresponding dose of Premarin alone. 20 (8) 1 (<1) , 9 (3) 1 (<1) Non-significant in comparison with corresponding dose of Premarin alone. 1 (<1) TABLE 8: OSTEOPOROSIS AND METABOLIC SUBSTUDY, INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCER All cases of hyperplasia/cancer were endometrial hyperplasia in patients who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study. AFTER TWO YEARS OF TREATMENT Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, a third pathologist adjudicated (consensus). -------------------------------Groups------------------------------ Patient Prempro 0.625 mg/2.5 mg Premarin 0.625 mg Prempro 0.45 mg/1.5 mg Premarin 0.45 mg Prempro 0.3 mg/1.5 mg Premarin 0.3 mg Total number of patients 75 65 75 74 79 73 Number of patients with evaluable biopsies 62 55 69 67 75 63 No. (%) of patients with biopsies: • Hyperplasia/cancer (consensus For an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least 2 pathologists had to agree on the diagnosis. ) 0 (0) Significant (p < 0.05) in comparison with corresponding dose of Premarin alone. 15 (27) 0 (0) 10 (15) 0 (0) 2 (3) 14.4 Effects on Uterine Bleeding or Spotting The effects of PREMPRO on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in 2 clinical trials. Results are shown in Figures 1 and 2. FIGURE 1. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING AT A GIVEN CYCLE THROUGH CYCLE 13 INTENT-TO-TREAT POPULATION, LOCF Note: The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF). FIGURE 2. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING AT A GIVEN CYCLE THROUGH CYCLE 13 INTENT-TO-TREAT POPULATION, LOCF Note: The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF). Figure 1 Figure 2 14.5 Effects on Bone Mineral Density Health and Osteoporosis, Progestin and Estrogen (HOPE) Study The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ± 0.9 years on average since menopause and took one 600 mg tablet of elemental calcium (Caltrate™) daily. Subjects were not given Vitamin D supplements. They were treated with PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg or 0.3 mg/1.5 mg, comparable doses of Premarin alone, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L 2 to L 4 ). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26. Intent-to-treat subjects All active treatment groups showed significant differences from placebo in each of the four BMD endpoints. These significant differences were seen at cycles 6, 13, 19, and 26. The percent changes from baseline to final evaluation are shown in Table 9. TABLE 9: PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION, LOCF Region Evaluated Treatment Group Identified by dosage (mg/mg) of Premarin/MPA or placebo. No. of Subjects Baseline (g/cm 2 ) Mean ± SD Change from Baseline (%) Adjusted Mean ± SE p-Value vs. Placebo L 2 to L 4 BMD 0.625/2.5 81 1.14 ± 0.16 3.28 ± 0.37 <0.001 0.45/1.5 89 1.16 ± 0.14 2.18 ± 0.35 <0.001 0.3/1.5 90 1.14 ± 0.15 1.71 ± 0.35 <0.001 Placebo 85 1.14 ± 0.14 -2.45 ± 0.36 Total body BMD 0.625/2.5 81 1.14 ± 0.08 0.87 ± 0.17 <0.001 0.45/1.5 89 1.14 ± 0.07 0.59 ± 0.17 <0.001 0.3/1.5 91 1.13 ± 0.08 0.60 ± 0.16 <0.001 Placebo 85 1.13 ± 0.08 -1.50 ± 0.17 Femoral neck BMD 0.625/2.5 81 0.89 ± 0.14 1.62 ± 0.46 <0.001 0.45/1.5 89 0.89 ± 0.12 1.48 ± 0.44 <0.001 0.3/1.5 91 0.86 ± 0.11 1.31 ± 0.43 <0.001 Placebo 85 0.88 ± 0.14 -1.72 ± 0.45 Femoral trochanter BMD 0.625/2.5 81 0.77 ± 0.14 3.35 ± 0.59 0.002 0.45/1.5 89 0.76 ± 0.12 2.84 ± 0.57 0.011 0.3/1.5 91 0.76 ± 0.12 3.93 ± 0.56 <0.001 Placebo 85 0.75 ± 0.12 0.81 ± 0.58 Figure 3 shows the cumulative percentage of subjects with percent changes from baseline in spine BMD equal to or greater than the percent change shown on the x-axis. FIGURE 3. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN/MPA AND PLACEBO GROUPS The mean percent changes from baseline in L 2 to L 4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 4. Significant differences between each of the PREMPRO dosage groups and placebo were found at cycles 6, 13, 19, and 26. FIGURE 4. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN/MPA GROUPS AND PLACEBO The bone turnover markers, serum osteocalcin and urinary N-telopeptide, significantly decreased (p < 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium; only with PREMPRO 0.625 mg/2.5 mg and 0.45 mg/1.5 mg were there significantly larger mean decreases than with placebo at 3 or more of the 4 time points. Figure 3 Figure 4 14.6 Women's Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 10. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 10: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. , Results are based on centrally adjudicated data. Relative Risk CE/MPA vs. Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE/MPA n = 8,506 Placebo n = 8,102 Event Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99–1.53) 41 34 Non-fatal MI 1.28 (1.00–1.63) 31 25 CHD death 1.10 (0.70–1.75) 8 8 All Strokes 1.31 (1.03–1.68) 33 25 Ischemic stroke 1.44 (1.09–1.90) 26 18 Deep vein thrombosis Not included in "global index." 1.95 (1.43–2.67) 26 13 Pulmonary embolism 2.13 (1.45–3.11) 18 8 Invasive breast cancer Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. 1.24 (1.01–1.54) 41 33 Colorectal cancer 0.61 (0.42–0.87) 10 16 Endometrial cancer 0.81 (0.48–1.36) 6 7 Cervical cancer 1.44 (0.47–4.42) 2 1 Hip fracture 0.67 (0.47–0.96) 11 16 Vertebral fractures 0.65 (0.46–0.92) 11 17 Lower arm/wrist fractures 0.71 (0.59–0.85) 44 62 Total fractures 0.76 (0.69–0.83) 152 199 Overall Mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83–1.19) 52 52 Global Index A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.13 (1.02–1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44–1.07)] . WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 11. Table 11: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Relative Risk CE vs. Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE n = 5,310 Placebo n = 5,429 Event Absolute Risk per 10,000 Women-Years CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78–1.16) 54 57 Non-fatal MI 0.91 (0.73–1.14) 40 43 CHD death 1.01 (0.71–1.43) 16 16 All Strokes 1.33 (1.05–1.68) 45 33 Ischemic stroke 1.55 (1.19–2.01) 38 25 Deep vein thrombosis , Not included in "global index." 1.47 (1.06–2.06) 23 15 Pulmonary embolism 1.37 (0.90–2.07) 14 10 Invasive breast cancer 0.80 (0.62–1.04) 28 34 Colorectal cancer Results are based on an average follow-up of 6.8 years. 1.08 (0.75–1.55) 17 16 Hip fracture 0.65 (0.45–0.94) 12 19 Vertebral fractures , 0.64 (0.44–0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47–0.72) 35 59 Total fractures , 0.71 (0.64–0.80) 144 197 Death due to other causes , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88–1.32) 53 50 Overall mortality , 1.04 (0.88–1.22) 79 75 Global Index A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92–1.13) 206 201 For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined. 10 Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36–1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–1.11)] . 14.7 Women's Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.5) ] . The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.5) ] . When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19–2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.5) ] .

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

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PREMPRO or PREMPHASE to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE. The Women's Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.6) ] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.6) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] .

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

8.4 Pediatric Use PREMPRO and PREMPHASE are not indicated in children. Clinical studies have not been conducted in the pediatric population.

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

8 USE IN SPECIFIC POPULATIONS • Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk ( 8.3 ) • Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative ( 5.3 , 8.5 ) 8.1 Pregnancy PREMPRO and PREMPHASE should not be used during pregnancy [see Contraindications (4) ] . There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy. 8.3 Nursing Mothers PREMPRO and PREMPHASE should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving these drugs. Caution should be exercised when PREMPRO or PREMPHASE is administered to a nursing woman. 8.4 Pediatric Use PREMPRO and PREMPHASE are not indicated in children. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PREMPRO or PREMPHASE to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE. The Women's Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.6) ] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.6) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] . 8.6 Renal Impairment The effects of renal impairment on the pharmacokinetics of PREMPRO or PREMPHASE have not been studied. 8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of PREMPRO or PREMPHASE have not been studied.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PREMPRO therapy consists of a single tablet to be taken once daily. PREMPRO 0.3 mg/1.5 mg NDC 0046-1105-11, carton includes 1 blister card containing 28 oval, cream tablets. PREMPRO 0.45 mg/1.5 mg NDC 0046-1106-11, carton includes 1 blister card containing 28 oval, gold tablets. PREMPRO 0.625 mg/2.5 mg NDC 0046-1107-11, carton includes 1 blister card containing 28 oval, peach tablets. PREMPRO 0.625 mg/5 mg NDC 0046-1108-11, carton includes 1 blister card containing 28 oval, light-blue tablets. PREMPHASE therapy consists of two separate tablets; one maroon Premarin tablet taken daily on days 1 through 14 and one light-blue tablet taken on days 15 through 28. NDC 0046-2575-12, carton includes 1 blister card containing 28 tablets (14 oval, maroon Premarin tablets and 14 oval, light-blue tablets). The appearance of PREMPRO tablets is a trademark of Pfizer Inc. The appearance of PREMARIN tablets is a trademark of Pfizer Inc. The appearance of the conjugated estrogens/medroxyprogesterone acetate combination tablets is a trademark. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.6 , 14.7) ] . The Women's 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 estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.6) ] . The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.7) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2) , and Clinical Studies (14.6) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and 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 Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.6 , 14.7) ] . 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 (14.6) ] . 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 (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.7) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA See full prescribing information for complete boxed warning. Estrogen Plus Progestin Therapy • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) • The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) ( 5.1 ) • The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.2 ) • The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Estrogen-Alone Therapy • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 ) • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) • The WHI estrogen-alone substudy reported increased risks of stroke and DVT ( 5.1 ) • The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 )