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CLINICAL PHARMACOLOGY 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, 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 follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Pharmacokinetics Absorption Estrogens are well absorbed through the skin and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. 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 sex hormone binding globulin (SHBG) and albumin. 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 proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Special Populations No pharmacokinetics studies were conducted in special populations, including patients with renal or hepatic impairment. Drug 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. Clinical Studies Effects On Postmenopausal Osteoporosis The results of a double-blind, placebo-controlled two-year study have shown that treatment with one tablet of OGEN 0.625 mg daily for 25 days (of a 31-day cycle per month) prevents vertebral bone mass loss in postmenopausal women. When estrogen-alone therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period. There is no evidence that estrogen-alone therapy restores bone mass to premenopausal levels. Women's Health Initiative Studies The Women's Health Initiative (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 coronary heart disease [(CHD) defined as nonfatal MI, silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. 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 to79; 75.3 percent White, 15 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 1. TABLE 1: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN- ALONE SUBSTUDY OF WHI* Event Relative Risk CE vs Placebo (95% nCI†) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events‡ 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‡,§ 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¶ 1.08 (0.75-1.55) 17 16 Hip fracture‡ 0.65 (0.45-0.94) 12 19 Vertebral fractures‡,§ 00.64(0.440.93) 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¶,# 1.08 (0.88–1.32) 53 50 Overall mortality‡,§ 1.04 (0.88–1.22) 79 75 Global IndexÞ 1.02 (0.92–1.13) 206 201 *Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. †Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ‡Results are based on centrally adjudicated data for an average follow-up of 7.1 years. §Not included in Global Index. ¶Results 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. ÞA 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. 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. 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 was present in all subgroups of women examined. 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 [hazard ration (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. 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 estrogen plus progestin 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 2. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 2: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS*,† Event Relative Risk CE/MPA vs Placebo (95% nCI‡) CE/MPA n = 8,506 Placebo n= 8,102 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§ 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive 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) 14 62 Total fractures§ 0.76 (0.69–0.83) 152 199 Overall mortality# 1.00 (0.83–1.19) 52 32 Global IndexÞ 1.13 (1.02–1.25) 184 165 *Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. †Results are based on centrally adjudicated data. ‡Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. §Not included in “global index”. ¶Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. #All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ÞA 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. 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 [HR 0.69 (95 percent CI, 0.44-1.07)]. Women's Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 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 Alzheimer 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, Probable Dementia and PRECAUTIONS, Geriatric Use.) The WHIMS estrogen plus progestin ancillary study 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 (0.625mg) 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 was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AS 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, Probable Dementia and PRECAUTIONS, Geriatric Use.) 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, Probable Dementia and PRECAUTIONS, Geriatric Use.)

Find Lowest Prices on OGEN® (estropipate) Tablets, USP WARNING ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA 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, Malignant Neoplasms, Endometrial cancer .) Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia. (See Clinical Studies and WARNINGS, Cardiovascular Disorders and Probable Dementia.) The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo. (See Clinical Studies and WARNINGS, Cardiovascular Disorders.) The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg) alone relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See Clinical Studies and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) 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. 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 Clinical Studies and WARNINGS, Cardiovascular Disorders and Probable Dementia.) The WHI estrogen plus progestin substudy reported increased risks of 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 CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See Clinical Studies and WARNINGS, Cardiovascular Disorders.) The 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 Clinical Studies and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See Clinical Studies and WARNINGS, Malignant Neoplasms, Breast Cancer.) 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. DESCRIPTION OGEN (estropipate tablets), (formerly piperazine estrone sulfate), is a natural estrogenic substance prepared from purified crystalline estrone, solubilized as the sulfate and stabilized with piperazine. It is appreciably soluble in water and has almost no odor or taste - properties which are ideally suited for oral administration. The amount of piperazine in OGEN is not sufficient to exert a pharmacological action. Its addition ensures solubility, stability, and uniform potency of the estrone sulfate. Chemically estropipate, molecular weight: 436.56, is represented by estra-1,3,5(10)-trien-17-one,3-(sulfooxy)-, compound with piperazine (1:1). The structural formula may be represented as follows: OGEN is available as tablets for oral administration containing either 0.75 mg (OGEN .625), 1.5 mg (OGEN 1.25), or 3 mg (OGEN 2.5) estropipate (Calculated as sodium estrone sulfate 0.625 mg, 1.25 mg, and 2.5 mg, respectively). Inactive Ingredients Each tablet contains: Colloidal silicon dioxide, dibasic potassium phosphate, hydrogenated vegetable oil wax, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and tromethamine. OGEN .625 also contains: D&C Yellow No. 10 and FD&C Yellow No. 6. OGEN 1.25 also contains: FD&C Yellow No. 6. OGEN 2.5 also contains: FD&C Blue No. 2.

INDICATIONS OGEN therapy is indicated in the: Treatment of moderate to severe vasomotor symptoms due to menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis non-estrogen medications should be carefully considered. The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg per day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU per day may also be required to ensure adequate daily intake in postmenopausal women. DOSAGE AND ADMINISTRATION When estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin. 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. Patients should be reevaluated periodically as clinically appropriate (for example at 3-month to 6-month intervals) to determine if treatment is still necessary. Adequate diagnostic measures, such as 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. For the treatment of moderate to severe vasomotor symptoms and/or moderate to severe vulvar and vaginal atrophy due to menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. Usual dosage ranges: Vasomotor symptoms-One OGEN .625 (0.75 mg estropipate) tablet to two OGEN 2.5 (3 mg estropipate) tablets per day. The lowest dose that will control symptoms should be chosen. If the patient has not menstruated within the last two months or more, cyclic administration is started arbitrarily. If the patient is menstruating, cyclic administration is started on day 5 of bleeding. Vulvar and vaginal atrophy-One OGEN .625 (0.75 mg estropipate) tablet to two OGEN 2.5 (3 mg estropipate) tablets daily, depending upon the tissue response of the individual patient. The lowest dose that will control symptoms should be chosen. Administer cyclically. When prescribing solely for the treatment of moderate to severe vulvar and vaginal atrophy, topical vaginal products should be considered. For the treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. Usual dosage ranges: Female hypogonadism-A daily dose of one OGEN 1.25 (1.5 mg estropipate) tablet to three OGEN 2.5 (3 mg estropipate) tablets may be given for the first three weeks of a theoretical cycle, followed by a rest period of eight to ten days. The lowest dose that will control symptoms should be chosen. If bleeding does not occur by the end of this period, the same dosage schedule is repeated. The number of courses of estrogen therapy necessary to produce bleeding may vary depending on the responsiveness of the endometrium. If satisfactory withdrawal bleeding does not occur, an oral progestogen may be given in addition to estrogen during the third week of the cycle. Female castration or primary ovarian failure- A daily dose of one OGEN 1.25 (1.5 mg estropipate) tablet to three OGEN 2.5 (3 mg estropipate) tablets may be given for the first three weeks of a theoretical cycle, followed by a rest period of eight to ten days. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding. For the prevention of postmenopausal osteoporosis. A daily dose of one OGEN .625 (0.75 mg estropipate) tablet for 25 days of a 31-day cycle per month. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered. HOW SUPPLIED OGEN (estropipate tablets, USP) is supplied as OGEN .625 (0.75 mg estropipate; calculated as sodium estrone sulfate 0.625 mg), yellow, scored tablets, imprinted U 3772, NDC 0009-3772-01; OGEN 1.25 (1.5 mg estropipate; calculated as sodium estrone sulfate 1.25 mg), peach-colored, scored tablets, imprinted U 3773, NDC 0009-3773-01; and OGEN 2.5 (3 mg estropipate; calculated as sodium estrone sulfate 2.5 mg), blue, scored tablets, imprinted U 3774, NDC 0009-3774-01. Tablets of all three dosage levels are standardized to provide uniform estrone activity and are scored to provide dosage flexibility. All tablet sizes of OGEN are available in bottles of 100. Recommended storage: Store below 77°F (25°C) Distributed by: Pharamacia & Upjohn Company, Divsion of Pfizer Inc., NY, NY 10017. Revised: Jul 2016.

PATIENT INFORMATION OGEN® (estropipate) Tablets, USP Read this PATIENT INFORMATION before you start taking OGEN and read what you get each time you refill your OGEN 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 I SHOULD KNOW ABOUT OGEN (AN ESTROGEN HORMONE)? Using estrogen-alone increases your chance of getting cancer of the uterus (womb) Report any unusual vaginal bleeding right away while you are taking OGEN. Vaginal bleeding after menopause may be a warning sign of cancer of the uterine (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function) Using estrogen-alone may increase your chances of getting strokes or blood clots Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older You and your healthcare provider should talk regularly about whether you still need treatment with OGEN What is OGEN? OGEN is a medicine that contains estropipate, an estrogen hormone. What is OGEN used for? OGEN is used after menopause to: Reduce moderate or severe hot flashes Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a 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”. When 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 to take estrogens. In other women, symptoms can be more severe. Treat menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with OGEN to control these problems. If you use OGEN only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. Help reduce your chances of getting osteoporosis (thin weak bones) Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use OGEN only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. Weight-bearing exercise, like walking or running, and taking calcium (1500 mg per day of elemental calcium) and vitamin D (400-800 IU per day) supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them. You and your healthcare provider should talk regularly about whether you still need treatment with OGEN. OGEN is also used to: Treat certain conditions in women before menopause if their ovaries do not make enough estrogen naturally Who should not take OGEN? Do not start taking OGEN if you: Have unusual vaginal bleeding Currently 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 have had cancer, talk with your healthcare provider about whether you should take OGEN. Had a stroke or heart attack Currently have or have had blood clots Currently have or have had liver problems Have been diagnosed with a bleeding disorder Are allergic to OGEN tablets or any of its ingredients See the list of ingredients at the end of this leaflet. Think you may be pregnant Tell your healthcare provider: If you have any unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. About all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. About all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how OGEN works. OGEN may also affect how your other medicines work. If you are going to have surgery or will be on bed rest You may need to stop taking OGEN. If you are breast feeding The hormone in OGEN can pass into your breast milk. How should I take OGEN? Take OGEN as directed by your healthcare provider. OGEN comes in three strengths. Check with your healthcare provider periodically to make sure you are using the appropriate dose. 1. Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. 2. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. The lowest effective dose of OGEN has not been determined. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with OGEN. What are the possible side effects of OGEN? Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: Heart attack Stroke Blood clots Dementia Breast cancer Cancer of the lining of the uterus (womb) Cancer of the ovary High blood pressure High blood sugar Gallbladder disease Liver problems Enlargement of benign tumors of the uterus (“fibroids”) Call you healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: New breast lumps Pharmacia and Upjohn Company LLC Unusual vaginal bleeding Changes in vision or speech Sudden new severe headaches Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue Less serious, but common side effects include: Headache Breast pain Irregular vaginal bleeding or spotting Stomach or abdominal cramps, bloating Nausea and vomiting Hair loss Fluid retention Vaginal yeast infection These are not all the possible side effects of OGEN. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What can I do to lower my chances of getting a serious side effect with OGEN? Talk with your healthcare provider regularly about whether you should continue taking OGEN If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb) See your healthcare provider right away if you get vaginal bleeding while taking OGEN Have a 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 examinations more often If 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 safe and effective use of OGEN Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take OGEN for conditions for which it was not prescribed. Do not give OGEN to other people, even if they have the same symptoms you have. It may harm them. Keep OGEN out of the reach of children. This leaflet provides a summary of the most important information about OGEN. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about OGEN that is written for health professionals. You can get more information by calling the toll free number 1-888-691-6813. What are the ingredients in OGEN? OGEN contains estropipate as the active ingredient. OGEN also contains colloidal silicon dioxide, dibasic potassium phosphate, hydrogenated vegetable oil wax, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and tromethamine. The color ingredients are: OGEN .625 (yellow tablet): D&C Yellow No. 10 and FD&C Yellow No. 6. OGEN 1.25 (peach tablet): FD&C Yellow No. 6. OGEN 2.5 (blue tablet): FD&C Blue No. 2.

WARNINGS See BOXED WARNINGS. Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a 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). See Clinical Studies.) The increase in risk was demonstrated in year 1 and persisted. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). In the WHI estrogen plus progestin a statistically significant increased risk of stroke was reported in women 50 to 79 years if 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.) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on CHD events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. (See Clinical Studies.) Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women less than 10 years since menopause (8 versus 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events 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). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years. (See Clinical Studies.) Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted. (See Clinical Studies.) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with an increased risk of 15-to-24 fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer 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 followup of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). (See Clinical Studies.) The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of 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 diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. (See Clinical Studies.) Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. Probable Dementia In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. (See Clinical Studies and PRECAUTIONS, Geriatric Use.) In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk 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. (See Clinical Studies and PRECAUTIONS, Geriatric Use.) 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 women. (See PRECAUTIONS, Geriatric Use.) Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. Visual Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. PRECAUTIONS General Addition Of A Progestin When A Woman Has Not Had A Hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. 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. Hepatic Impairment and/or Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving 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 levels in an acceptable range. Fluid Retention Estrogens may cause some degree of fluid retention. Women who have conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. Hypocalcemia Estrogen therapy should be used with caution in individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Exacerbation of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis posthysterectomy, the addition of progestin should be considered. Exacerbation of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Information For Patients Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe OGEN. Laboratory Tests Serum 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. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure. Carcinogenesis, Mutagenesis, Impairment Of Fertility (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. Pregnancy OGEN should not be used during pregnancy. (See CONTRAINDICATIONS.) 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. Nursing Mothers OGEN 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 estrogens have been identified in the breast milk of women receiving estrogen. Caution should be exercised when OGEN is administered to a nursing woman. Pediatric Use OGEN is not indicated in children. Clinical studies have not been conducted in the pediatric population. Geriatric Use There have not been sufficient numbers of geriatric patients involved in studies utilizing OGEN to determine whether those over 65 years of age differ from younger subjects in their response to OGEN. The Women's Health Initiative Study 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.) 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.) 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-alone or estrogen plus progestin when compared to placebo. (See Clinical Studies and WARNINGS, Probable Dementia.) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See Clinical Studies and WARNINGS, Probable Dementia.)