Prempro
conjugated estrogens and medroxyprogesterone acetate · Tablet, Sugar Coated · Oral
Uses
1 INDICATIONS AND USAGE PREMPRO/PREMPHASE is an estrogen plus progestin indicated in a woman with a uterus for:
• Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 )
• Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause ( 1.2 )
• Prevention of Postmenopausal Osteoporosis ( 1.3 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause 1.3 Prevention of Postmenopausal Osteoporosis
Dosage and administration
Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. PREMPRO: one tablet containing conjugated estrogens (CE) plus medroxyprogesterone acetate (MPA) taken orally once daily. ( 2 ) PREMPHASE: one maroon tablet containing 0.625 mg CE taken orally on days 1 through 14, and one light-blue tablet containing 0.625 mg CE plus 5.0 mg MPA taken orally on days 15 through 28. ( 2 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause PREMPRO therapy consists of a single tablet to be taken orally once daily. PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg Premarin [conjugated estrogens (CE)] tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg of medroxyprogesterone acetate (MPA) taken on days 15 through 28. 2.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause PREMPRO therapy consists of a single tablet to be taken orally once daily. PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg CE tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg MPA taken on days 15 through 28. When prescribing solely for the treatment of moderate to severe vulvar and vaginal atrophy, topical vaginal products should be considered. 2.3 Prevention of Postmenopausal Osteoporosis PREMPRO therapy consists of a single tablet to be taken orally once daily. PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg CE tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg of MPA taken on days 15 through 28. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.
Dosage forms and strengths
(conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.3 mg CE plus 1.5 mg MPA oval/cream PREMPRO 0.3/1.5 0.45 mg CE plus 1.5 mg MPA oval/gold PREMPRO 0.45/1.5 0.625 mg CE plus 2.5 mg MPA oval/peach PREMPRO 0.625/2.5 0.625 mg CE plus 5 mg MPA oval/light blue PREMPRO 0.625/5 PREMPHASE (conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.625 mg CE oval/maroon (14 tablets) PREMARIN 0.625 0.625 mg CE plus 5 mg MPA oval/light-blue (14 tablets) PREMPRO 0.625/5 PREMPRO Tablets: 0.3 mg CE plus 1.5 mg MPA, 0.45 mg CE plus 1.5 mg MPA, 0.625 mg CE plus 2.5 mg MPA, 0.625 mg CE plus 5 mg MPA. PREMPHASE Tablets: 0.625 mg CE, 0.625 mg CE plus 5 mg MPA.
Contraindications
4 CONTRAINDICATIONS PREMPRO and PREMPHASE are contraindicated in women with any of the following conditions:
• Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2) ]
• Breast cancer or a history of breast cancer [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 PREMPRO/PREMPHASE [see Warnings and Precautions (5.15 , 5.16 )]
• Hepatic impairment or disease [see Warnings and Precautions (5.10) ]
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
• Undiagnosed abnormal genital bleeding ( 4 )
• Breast cancer or history of breast cancer ( 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 to PREMPRO/PREMPHASE ( 5.15 , 5.16 )
• Hepatic impairment or disease ( 4 , 5.10 )
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )
Warnings and precautions
• Estrogens increase the risk of gallbladder disease ( 5.4 )
• Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.9 , 5.10 )
• Monitor thyroid function in women on thyroid replacement therapy ( 5.11 , 5.19 ) 5.1 Cardiovascular Disorders An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies (14.6) ] . The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in Year 1 and persisted [see Clinical Studies (14.6) ] . Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.6) ] . In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.6) ] . 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 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 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 (VTE) In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted 3 [see Clinical Studies (14.6) ] . Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years 4 [see Clinical Studies (14.6) ] . Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 5.2 Malignant Neoplasms Breast Cancer The 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 (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] 5 [see Clinical Studies (14.6)] . 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.
Side effects
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.
Drug 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'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.
Use in specific populations
• Lactation: Estrogen administration to lactating women has been shown to decrease the quantity and quality of breast milk ( 8.2 )
• Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative ( 5.3 , 8.5 ) 8.1 Pregnancy Risk Summary PREMPRO and PREMPHASE are not indicated for use during pregnancy. There are no data with the use of PREMPRO and PREMPHASE in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens and progestins and metabolites are present in human milk. These hormones can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for PREMPRO or PREMPHASE and any potential adverse effects on the breast-fed child from PREMPRO or PREMPHASE or from the underlying maternal condition. 8.4 Pediatric Use PREMPRO and PREMPHASE are not indicated in children. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PREMPRO or PREMPHASE to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE. The Women's Health Initiative Study In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.6) ] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.6) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] . 8.6 Renal Impairment The effects of renal impairment on the pharmacokinetics of PREMPRO or PREMPHASE have not been studied. 8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of PREMPRO or PREMPHASE have not been studied.
Pregnancy
8.1 Pregnancy Risk Summary PREMPRO and PREMPHASE are not indicated for use during pregnancy. There are no data with the use of PREMPRO and PREMPHASE in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pediatric use
8.4 Pediatric Use PREMPRO and PREMPHASE are not indicated in children. Clinical studies have not been conducted in the pediatric population.
Geriatric use
8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PREMPRO or PREMPHASE to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE. The Women's Health Initiative Study In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.6) ] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.6) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.3) , and Clinical Studies (14.7) ] .
Overdosage
Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of PREMPRO or PREMPHASE therapy with institution of appropriate symptomatic care.
Description
Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol and 17 β-dihydroequilin. Medroxyprogesterone acetate is a derivative of progesterone. It is a white to off-white, odorless, crystalline powder, stable in air, melting between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water. The chemical name for MPA is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. Its molecular formula is C 24 H 34 O 4 , with a molecular weight of 386.53. Its structural formula is: PREMPRO 0.3 mg/1.5 mg and 0.45 mg/1.5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, microcrystalline cellulose, carnauba wax, hypromellose, hydroxypropyl cellulose, sucrose, Eudragit NE 30D, lactose monohydrate, magnesium stearate, polyethylene glycol, titanium dioxide, yellow iron oxide, propylene glycol and black iron oxide. PREMPRO 0.625 mg/2.5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, microcrystalline cellulose, carnauba wax, hypromellose, hydroxypropyl cellulose, sucrose, Eudragit NE 30D, lactose monohydrate, magnesium stearate, polyethylene glycol, propylene glycol, titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide. PREMPRO 0.625 mg/5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, carnauba wax, Eudragit NE 30D, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, titanium dioxide, triethyl citrate, FD&C Blue No. 2, black iron oxide, and propylene glycol. PREMPHASE Each maroon Premarin tablets for oral administration contain 0.625 mg of 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
Mechanism of action
12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women. Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation; although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue. Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity.
How supplied
16.1 How Supplied PREMPRO therapy consists of a single tablet to be taken once daily. PREMPRO 0.3 mg/1.5 mg NDC 0046-1105-11, carton includes 1 blister card containing 28 oval, cream tablets. PREMPRO 0.45 mg/1.5 mg NDC 0046-1106-11, carton includes 1 blister card containing 28 oval, gold tablets. PREMPRO 0.625 mg/2.5 mg NDC 0046-1107-11, carton includes 1 blister card containing 28 oval, peach tablets. PREMPRO 0.625 mg/5 mg NDC 0046-1108-11, carton includes 1 blister card containing 28 oval, light-blue tablets. PREMPHASE therapy consists of two separate tablets; one maroon Premarin tablet taken daily on days 1 through 14 and one light-blue tablet taken on days 15 through 28. NDC 0046-2575-12, carton includes 1 blister card containing 28 tablets (14 oval, maroon Premarin tablets and 14 oval, light-blue tablets). The appearance of PREMPRO tablets is a trademark of Pfizer Inc. The appearance of PREMARIN tablets is a trademark of Pfizer Inc. The appearance of the conjugated estrogens/medroxyprogesterone acetate combination tablets is a trademark. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. 16.1 How Supplied PREMPRO therapy consists of a single tablet to be taken once daily. PREMPRO 0.3 mg/1.5 mg NDC 0046-1105-11, carton includes 1 blister card containing 28 oval, cream tablets. PREMPRO 0.45 mg/1.5 mg NDC 0046-1106-11, carton includes 1 blister card containing 28 oval, gold tablets. PREMPRO 0.625 mg/2.5 mg NDC 0046-1107-11, carton includes 1 blister card containing 28 oval, peach tablets. PREMPRO 0.625 mg/5 mg NDC 0046-1108-11, carton includes 1 blister card containing 28 oval, light-blue tablets. PREMPHASE therapy consists of two separate tablets; one maroon Premarin tablet taken daily on days 1 through 14 and one light-blue tablet taken on days 15 through 28. NDC 0046-2575-12, carton includes 1 blister card containing 28 tablets (14 oval, maroon Premarin tablets and 14 oval, light-blue tablets). The appearance of PREMPRO tablets is a trademark of Pfizer Inc. The appearance of PREMARIN tablets is a trademark of Pfizer Inc. The appearance of the conjugated estrogens/medroxyprogesterone acetate combination tablets is a trademark.
Patient information
Advise the patients to read the FDA-approved Patient Labeling (Patient Information). 17.1 Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2) ] . 17.2 Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . 17.3 Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.
Label text from the FDA structured product label by Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. (revised Apr 28, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Estrogens, Conjugated in 4 products
- Medroxyprogesterone Acetate in 4 products
Prempro NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0046-1105 | Estrogens, Conjugated .3 mg/1; Medroxyprogesterone Acetate 1.5 mg/1 Tablet, Sugar Coated | Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. | NDA |
| 0046-1106 | Estrogens, Conjugated .45 mg/1; Medroxyprogesterone Acetate 1.5 mg/1 Tablet, Sugar Coated | Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. | NDA |
| 0046-1107 | Estrogens, Conjugated .625 mg/1; Medroxyprogesterone Acetate 2.5 mg/1 Tablet, Sugar Coated | Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. | NDA |
| 0046-1108 | Estrogens, Conjugated .625 mg/1; Medroxyprogesterone Acetate 5 mg/1 Tablet, Sugar Coated | Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. | NDA |
Frequently asked questions
What is Prempro used for?
1 INDICATIONS AND USAGE PREMPRO/PREMPHASE is an estrogen plus progestin indicated in a woman with a uterus for: • Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) • Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) • Prevention of Postmenopausal Osteoporosis ( 1.3 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause…
What are the side effects of Prempro?
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,… See the full label for the complete list.
Who makes Prempro?
Prempro is listed by 1 labeler in the FDA NDC directory, including Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc..