ESTROGENS, CONJUGATED: 9,135 Adverse Event Reports & Safety Profile

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 CE 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 CE, 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

AND USAGE Conjugated estrogens tablets is a mixture of estrogens indicated 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 )
• Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure ( 1.3 )
• Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease ( 1.4 )
• Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) ( 1.5 )
• Prevention of Postmenopausal Osteoporosis ( 1.6 )

1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitations of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.

1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure

1.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease

1.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only)

1.6 Prevention of Postmenopausal Osteoporosis Limitations of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

AND ADMINISTRATION Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer [see Boxed Warning ]. A woman without a uterus does not need progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see Warnings and Precautions (5.2, 5.16) ] . 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. Conjugated estrogens tablets may be taken without regard to meals.

• Daily administration of 0.3 mg, 0.45 mg, and 0.625 mg ( 2.1 , 2.2 , 2.3 , 2.5 , 2.6 )
• Cyclic administration of 0.3 mg, and 0.625 mg ( 2.1 , 2.2 , 2.3 )

2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg conjugated estrogens tablets daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. Conjugated estrogens tablets therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis.

2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg conjugated estrogens tablets daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider. Conjugated estrogens tablets therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis.

2.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure Conjugated estrogens tablets therapy should be initiated and maintained with the lowest effective dose to achieve clinical goals. Female hypogonadism: 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium [ see Clinical Studies (14.4) ]. Female castration or primary ovarian failure: 1.25 mg daily, cyclically. 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.

2.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease Suggested dosage is 10 mg three times daily, for a period of at least three months.

2.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) 2x0.625 mg to 4x0.625 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

2.6 Prevention of Postmenopausal Osteoporosis Conjugated estrogens tablets therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically appropriate on an individual basis. Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg conjugated estrogens tablets daily. Subsequent dosage adjustment may be made based upon the individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider.

Conjugated estrogens tablets therapy is contraindicated in individuals with any of the following conditions:

• Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )]
• Breast cancer or a history of breast cancer except in appropriately selected patients being treated for metastatic disease [see Warnings and Precautions ( 5.2 )]
• Estrogen-dependent neoplasia [see Warnings and Precautions ( 5.2 )]
• Active DVT, PE, or a history of these conditions [see Warnings and Precautions ( 5.1 )]
• Active arterial thromboembolic disease (for example stroke and MI), or a history of these conditions [see Warnings and Precautions ( 5.1 )]
• Known anaphylactic reaction or angioedema with conjugated estrogens tablets [see Warnings and Precautions ( 5.7 , 5.15 )]
• Hepatic impairment or disease [see Warnings and Precautions ( 5.11 )]
• Protein C, protein S or antithrombin deficiency, or other known thrombophilic disorders.
• Undiagnosed abnormal genital bleeding ( 4 )
• Breast cancer or history of breast cancer except in appropriately selected patients being treated for metastatic diseases ( 4 , 5.2 )
• 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 with conjugated estrogens tablets ( 5.7 , 5.15 )
• Hepatic impairment or disease ( 4 , 5.11 )
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

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% 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%, see Table 1 .

Table

1: Treatment-Related Adverse Reactions at a Frequency ≥1% 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%) 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% 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% in at least 1 treatment group.

Table

2: All Treatment-Related Adverse Reactions at a Frequency of ≥1% 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%, 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.

AND PRECAUTIONS

• Estrogens increase the risk of gallbladder disease ( 5.5 )
• Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.6 , 5.7 , 5.10 , 5.11 )
• Monitor thyroid function in women on thyroid replacement therapy ( 5.12 , 5.21 )

5.1 Risks from Systemic Absorption Systemic absorption occurs with the use of PREMARIN vaginal cream. The warnings, precautions, and adverse reactions associated with oral PREMARIN treatment should be taken into account.

5.2 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). The increase in risk was demonstrated in Year 1 and persisted <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) -alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> . The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

Coronary Heart

Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.2) ] . Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years). 1 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1 An increase in relative risk was demonstrated in Year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.2) ]. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in Year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall.

Venous

Thromboembolism (VTE) 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 3 [see Clinical Studies (14.2) ] . 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 4 [see Clinical Studies (14.2) ] . 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.

5.3 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 to be associated with prolonged use, with increased risks 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 postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. In a 52-week clinical trial using PREMARIN vaginal cream alone (0.5 g inserted twice weekly or daily for 21 days, then off for 7 days), there was no evidence of endometrial hyperplasia or endometrial carcinoma.

Breast Cancer

The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] 5 [see Clinical Studies (14.2) ] . After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at 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 6 [see Clinical Studies (14.2) ] . Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy and a smaller increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to > 10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. 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% confidence interval [CI], 0.77–3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. 7 A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% CI 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27–1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

5.4 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% 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 8 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) , and Clinical Studies (14.3) ]</span> . In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95% 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 8 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) , and Clinical Studies (14.3) ]</span> . 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% CI, 1.19–2.60). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) , and Clinical Studies (14.3) ]</span> .

5.5 Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5.6 Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

5.7 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.

5.8 Addition of a Progestin When a Woman Has Not Had a Hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

5.9 Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.

5.10 Exacerbation of Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.

5.11 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.

5.12 Exacerbation of Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T 4 and T 3 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.

5.13 Fluid Retention Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

5.14 Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

5.15 Exacerbation of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

5.16 Anaphylactic Reaction and Angioedema Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered PREMARIN and require emergency management, have been reported in the postmarketing setting. Skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted. Angioedema involving the tongue, larynx, face, and feet requiring medical intervention has occurred postmarketing in patients taking orally-administered PREMARIN. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with oral PREMARIN should not receive oral PREMARIN again.

5.17 Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

5.18 Exacerbation of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

5.19 Effects on Barrier Contraception PREMARIN vaginal cream exposure has been reported to weaken latex condoms. The potential for PREMARIN vaginal cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.

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

5.21 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 anti-factor 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, reduced low-density lipoprotein (LDL) cholesterol, increased triglyceride levels.
• Impaired glucose tolerance.

PRECAUTIONS A.

General Premarin

Intravenous for injection is indicated for short-term use. However, warnings, precautions and adverse reactions associated with oral Premarin treatment should be taken into account. 1. 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 which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. 2. Elevated blood pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. 3. 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. 4. 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. 5.

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 T 4 and T 3 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. 6. Fluid retention Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7.

Hypocalcemia

Estrogen therapy should be used with caution in individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. 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. B.

Patient Information

Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients who are being treated with Premarin Intravenous. C.

Laboratory Tests

Estrogen administration should be guided by clinical response at the lowest dose, rather than laboratory monitoring. D. Drug-Laboratory Test Interactions 1. 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 anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), 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). 4. Increased plasma high-density lipoprotein (HDL) and HDL 2 subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels. 5. Impaired glucose tolerance. E. Carcinogenesis, Mutagenesis, and 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. F.

Pregnancy Premarin

Intravenous should not be used during pregnancy. (See CONTRAINDICATIONS .) G.

Nursing Mothers Premarin

Intravenous 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 estrogens. Caution should be exercised when Premarin Intravenous is administered to a nursing woman. H.

Pediatric Use

Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. I.

Geriatric Use

There have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ from younger subjects in their response to Premarin.

The

Women's Health Initiative Studies 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 .)

INTERACTIONS Data from a single-dose drug-drug interaction study involving CE and MPA 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&apos;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.

ACTIVE INGREDIENTS Estrogen 9X, 12X, 30X, 60X

INACTIVE INGREDIENTS 20% ethanol, purified water.