Prempro conjugated estrogens and medroxyprogesterone acetate .45 mg; 1.5 mg Tablet, Sugar Coated, 28-count — NDC 0046-1106-11 (Billing 00046-1106-11)
This is a package of 28 tablets of Prempro conjugated estrogens and medroxyprogesterone acetate .45 mg; 1.5 mg Tablet, Sugar Coated from Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc., marketed since Sep 2009 and currently FDA-listed; retail pharmacies pay about $8.68 per tablet (NADAC). It is this product's only package size.
NDC database record
One package, one record: these facts belong to NDC 0046-1106-11 alone.
- Record
- FDA NDC Directory package listing · Human prescription drug
- Code segments
- 0046 labeler · 1106 product · 11 package
- Package marketed since
- Sep 21, 2009
- Sample package
- No — commercial package
- Listing certified through
- Dec 31, 2027
- Billing quantity
- 28 EA per package
- Barcode (UPC-A, from the NDC)
- 3 0046110611 3
- Medicaid fills, this package
- 7,608 prescriptions in the last four reported quarters
- FDA record last changed
- Sep 17, 2026
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 052179
- GCN: 19739
- GPI-14 (Medi-Span): 24993002040345
- HICL (First Databank): 009649
- AHFS class code: 68:16.04.00
- RxCUI (RxNorm): 150840
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 3, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Estrogen class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
- It is for women who still have a uterus. It treats moderate to severe menopause hot flashes and vaginal dryness and thinning, and it helps prevent osteoporosis after menopause. If...
- Prempro is one tablet by mouth once a day. Premphase uses two different tablets, one for days 1 through 14 and another for days 15 through 28. Follow your prescriber's directions a...
- The most common ones are abdominal pain, headache, breast pain, nausea, gas, back pain, tiredness and itching. Mention them to me or your doctor if they bother you or don't go away...
- Get emergency help for signs of stroke, heart attack or a blood clot, such as sudden weakness, chest pain, shortness of breath or leg swelling. Sudden vision loss, yellowing of the...
Patient education
Supplement & herbal interactions
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 3, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $8.684 | $243.14 / 28 tablets |
| Medicaid paysCMS SDUD · 12 mo | $8.68 | $243.10 / 28 tablets |
| Medicare drug plans payPart D · Q2 2026 | $8.94 | $250.23 / 28 tablets |
Where does this data come from?
- CMS NADAC weekly file · file of Sep 30, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 00046-1106-11 You're viewing this Main listing | 1 BLISTER PACK in 1 CARTON / 28 TABLET, SUGAR COATED in 1 BLISTER PACK | 2009-09-21 | — | Active |
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Prempro .45 mg/1; 1.5 mgthis 00046-1106-11 | Wyeth | 28 tablets | $8.684 | — | Availability likely | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Oct 3, 2026
- CMS NADAC weekly file · file of Sep 30, 2026
Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route.
Where does this data come from?
- FDA Orange Book · refreshed Oct 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 3, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
Where does this data come from?
IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.- FDA label on DailyMed · label index refreshed Oct 3, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
Why might an inactive ingredient be missing?
Can inactive ingredients matter?
Manufacturer & labeler
More NDCs from Wyeth Pharmaceuticals LLC, a subsidiary of Pfize... labeler code 00046
- Premarin estrogens, conjugated .3 mg Tablet, Film Coated NDC 0046-1100-52
- Premarin estrogens, conjugated .45 mg Tablet, Film Coated NDC 0046-1101-81
- Premarin estrogens, conjugated .625 mg Tablet, Film Coated NDC 0046-1102-52
- Premarin estrogens, conjugated .9 mg Tablet, Film Coated NDC 0046-1103-81
- Premarin estrogens, conjugated 1.25 mg Tablet, Film Coated NDC 0046-1104-81
- Prempro conjugated estrogens and medroxyprogesterone acetate .3 mg; 1.5 mg Tablet, Sugar Coated NDC 0046-1105-11
- Prempro conjugated estrogens and medroxyprogesterone acetate .625 mg; 2.5 mg Tablet, Sugar Coated NDC 0046-1107-11
- Prempro conjugated estrogens and medroxyprogesterone acetate .625 mg; 5 mg Tablet, Sugar Coated NDC 0046-1108-11
- Premphase conjugated estrogens and medroxyprogesterone acetate Kit NDC 0046-2575-12
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.6 , 14.7) ] . The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) (0.625 mg) combined with medroxyprogesterone acetate (MPA) (2.5 mg), relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.6) ] .
The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.7) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2) , and Clinical Studies (14.6) ] .
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.
Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.6 , 14.7) ] .
The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.6) ] . The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.7) ] .
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA See full prescribing information for complete boxed warning.
Estrogen Plus Progestin Therapy • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) • The Women's Health I… [Excerpted — this section continues on DailyMed.]
🎯 Indications and Usage ▾
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 ▾
2 DOSAGE AND ADMINISTRATION Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. PREMPRO: one tablet containing conjugated estrogens (CE) plus medroxyprogesterone acetate (MPA) taken orally once daily.
( 2 ) PREMPHASE: one maroon tablet containing 0.625 mg CE taken orally on days 1 through 14, and one light-blue tablet containing 0.625 mg CE plus 5.0 mg MPA taken orally on days 15 through 28. ( 2 )
2.1Treatment 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.
2.2Treatment 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.
2.3Prevention 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 ▾
3 DOSAGE FORMS AND STRENGTHS PREMPRO (conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.3 mg CE plus 1.5 mg MPA oval/cream PREMPRO 0.3/1.5 0.45 mg CE plus 1.5 mg MPA oval/gold PREMPRO 0.45/1.5 0.625 mg CE plus 2.5 mg MPA oval/peach PREMPRO 0.625/2.5 0.625 mg CE plus 5 mg MPA oval/light blue PREMPRO 0.625/5 PREMPHASE (conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.625 mg CE oval/maroon (14 tablets) PREMARIN 0.625 0.625 mg CE plus 5 mg MPA oval/light-blue (14 tablets) PREMPRO 0.625/5 PREMPRO Tablets: 0.3 mg CE plus 1.5 mg MPA, 0.45 mg CE plus 1.5 mg MPA, 0.625 mg CE plus 2.5 mg MPA, 0.625 mg CE plus 5 mg MPA.
PREMPHASE Tablets: 0.625 mg CE, 0.625 mg CE plus 5 mg MPA.
⛔ 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 Cautions ▾
5 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 )
5.1Cardiovascular 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… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] • Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] In two prospective, randomized clinical studies, the most common adverse reactions >5% 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 .
6.1Clinical 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… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 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 )
7.1Metabolic 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.
🔄 Drug / Laboratory Test Interactions ▾
5.19Drug-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.
👥 Use in Specific Populations ▾
8 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 )
8.1Pregnancy 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.
8.2Lactation 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.
8.4Pediatric Use PREMPRO and PREMPHASE are not indicated in children. Clinical studies have not been conducted in the pediatric population.
8.5Geriatric 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) ] .
8.6Renal Impairment The effects of renal impairment on the pharmacokinetics of PREMPRO or PREMPHASE have not been studied.
8.7Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of PREMPRO or PREMPHASE have not been studied.
🤰 Pregnancy ▾
8.1Pregnancy 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 ▾
8.4Pediatric Use PREMPRO and PREMPHASE are not indicated in children. Clinical studies have not been conducted in the pediatric population.
🧓 Geriatric Use ▾
8.5Geriatric 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 ▾
10 OVERDOSAGE Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of PREMPRO or PREMPHASE therapy with institution of appropriate symptomatic care.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle.
After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.
To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism.
Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women. Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation; although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue.
Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity.
12.2Pharmacodynamics Currently, there are no pharmacodynamic data known for PREMPRO or PREMPHASE tablets.
12.3Pharmacokinetics Absorption PREMPRO and PREMPHASE contain a formulation of medroxyprogesterone acetate (MPA) that is immediately released and CE that are slowly released over several hours. Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. MPA is well absorbed from the gastrointestinal tract.
Table 3 and Table 4 summarize the mean pharmacokinetic parameters for select unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of PREMPRO to healthy, postmenopausal women. Table 3: Pharmacokinetic Parameters for Unconjugated and Conjugated Estrogens (CE) and Medroxyprogesterone Acetate (MPA) BA* = Baseline adjusted C max = peak plasma concentration t max = time peak concentration occurs t 1/2 = apparent terminal-phase disposition half-life (0.693/λ z ) AUC = total area under the concentration-time curve DRUG 2 × 0.625 mg CE/2.5 mg MPA Combination Tablets (n = 54) 2 × 0.625 mg CE/5 mg MPA Combination Tablets (n = 51) PK Parameter Arithmetic Mean (%CV) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) Unconjugated Estrogens Estrone 175 (23) 7.6 (24) 31.6 (23) 5358 (34) 124 (43) 10 (35) 62.2 (137) 6303 (40) BA* -Estrone 159 (26) 7.6 (24) 16.9 (34) 3313 (40) 104 (49) 10 (35) 26.0 (100) 3136 (51) Equilin 71 (31) 5.8 (34) 9.9 (35) 951 (43) 54 (43) 8.9 (34) 15.5 (53) 1179 (56) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Conjugated Estrogens Total Estrone 6.6 (38) 6.1 (28) 20.7 (34) 116 (59) 6.3 (48) 9.1 (29) 23.6 (36) 151 (42) BA* -Total Estrone 6.4 (39) 6.1 (28) 15.4 (34) 100 (57) 6.2 (48) 9.1 (29) 20.6 (35) 139 (40) Total Equilin 5.1 (45) 4.6 (35) 11.4 (25) 50 (70) 4.2 (52) 7.0 (36) 17.2 (131) 72 (50) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism 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 / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1How 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.
16.2Storage 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].
16.1How 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.
📋 Description ▾
11 DESCRIPTION Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol and 17 β-dihydroequilin.
Medroxyprogesterone acetate is a derivative of progesterone. It is a white to off-white, odorless, crystalline powder, stable in air, melting between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water.
The chemical name for MPA is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. Its molecular formula is C 24 H 34 O 4 , with a molecular weight of 386.53. Its structural formula is: PREMPRO 0.3 mg/1.5 mg and 0.45 mg/1.5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, microcrystalline cellulose, carnauba wax, hypromellose, hydroxypropyl cellulose, sucrose, Eudragit NE 30D, lactose monohydrate, magnesium stearate, polyethylene glycol, titanium dioxide, yellow iron oxide, propylene glycol and black iron oxide.
PREMPRO 0.625 mg/2.5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, microcrystalline cellulose, carnauba wax, hypromellose, hydroxypropyl cellulose, sucrose, Eudragit NE 30D, lactose monohydrate, magnesium stearate, polyethylene glycol, propylene glycol, titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide. PREMPRO 0.625 mg/5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, carnauba wax, Eudragit NE 30D, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, titanium dioxide, triethyl citrate, FD&C Blue No.
2, black iron oxide, and propylene glycol. PREMPHASE Each maroon Premarin tablets for oral administration contain 0.625 mg of 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
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patients to read the FDA-approved Patient Labeling (Patient Information).
17.1Abnormal 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) ] .
17.2Possible 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) ] .
17.3Possible 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.
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics Absorption PREMPRO and PREMPHASE contain a formulation of medroxyprogesterone acetate (MPA) that is immediately released and CE that are slowly released over several hours. Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. MPA is well absorbed from the gastrointestinal tract.
Table 3 and Table 4 summarize the mean pharmacokinetic parameters for select unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of PREMPRO to healthy, postmenopausal women. Table 3: Pharmacokinetic Parameters for Unconjugated and Conjugated Estrogens (CE) and Medroxyprogesterone Acetate (MPA) BA* = Baseline adjusted C max = peak plasma concentration t max = time peak concentration occurs t 1/2 = apparent terminal-phase disposition half-life (0.693/λ z ) AUC = total area under the concentration-time curve DRUG 2 × 0.625 mg CE/2.5 mg MPA Combination Tablets (n = 54) 2 × 0.625 mg CE/5 mg MPA Combination Tablets (n = 51) PK Parameter Arithmetic Mean (%CV) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) Unconjugated Estrogens Estrone 175 (23) 7.6 (24) 31.6 (23) 5358 (34) 124 (43) 10 (35) 62.2 (137) 6303 (40) BA* -Estrone 159 (26) 7.6 (24) 16.9 (34) 3313 (40) 104 (49) 10 (35) 26.0 (100) 3136 (51) Equilin 71 (31) 5.8 (34) 9.9 (35) 951 (43) 54 (43) 8.9 (34) 15.5 (53) 1179 (56) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Conjugated Estrogens Total Estrone 6.6 (38) 6.1 (28) 20.7 (34) 116 (59) 6.3 (48) 9.1 (29) 23.6 (36) 151 (42) BA* -Total Estrone 6.4 (39) 6.1 (28) 15.4 (34) 100 (57) 6.2 (48) 9.1 (29) 20.6 (35) 139 (40) Total Equilin 5.1 (45) 4.6 (35) 11.4 (25) 50 (70) 4.2 (52) 7.0 (36) 17.2 (131) 72 (50) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Medroxyprogesterone Acetate MPA 1.5 (40) 2.8 (54) 37.6 (30) 37 (30) 4.8 (31) 2.4 (50) 46.3 (39) 102 (28) TABLE 4.
Pharmacokinetic Parameters for Unconjugated and Conjugated Estrogens (CE) and Medroxyprogesterone Acetate (MPA) BA* = Baseline adjusted C max = peak plasma concentration t max = time peak concentration occurs t 1/2 = apparent terminal-phase disposition half-life (0.693/λ z ) AUC = total area under the concentration-time curve DRUG 4 × 0.45 mg CE/1.5 mg MPA Combination (n = 65) PK Parameter Arithmetic Mean (%CV) C max (pg/mL) t max (h) t 1/2 (h) AUC (pg∙h/mL) Unconjugated Estrogens Estrone 149 (35) 8.9 (35) 37.5 (35) 6641 (39) BA* -Estrone 130 (40) 8.9 (35) 21.2 (35) 3799 (47) Equilin 83 (38) 8.3 (48) 15.9 (44) 1889 (40) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Conjugated Estrogens Total Estrone 5.4 (49) 7.9 (48) 22.4 (53) 119 (48) BA* -Total Estrone 5.2 (48) 7.9 (48) 15.1 (29) 100 (47) Total Equilin 4.3 (42) 6.5 (45) 11.6 (31) 74 (48) PK Parameter Arithmetic Mean (%CV) C max (ng/mL) t max (h) t 1/2 (h) AUC (ng∙h/mL) Medroxyprogesterone Acetate MPA 0.7 (66) 2.0 (52) 26.2 (35) 5.0 (61) Food-Effect: Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when PREMPRO or PREMPHASE is administered with a high-fat breakfast.
Administration with food decreased the C max of total estrone by 18 to 34% and increased total equilin C max by 38% compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA C max and increases MPA AUC by approximately 20 to 30%. Dose Proportionality: The C max and AUC values for MPA observed in two separate pharmacokinetic studies conducted with 2 PREMPRO 0.625 mg/2.5 mg or 2 PREMPRO or PREMPHASE 0.625 mg/5 mg tablets exhibited nonlinear dose proportionality; doubling the MPA dose from 2 × 2.5 to 2 × 5 mg… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Currently, there are no pharmacodynamic data known for PREMPRO or PREMPHASE tablets.
🔬 Clinical Studies ▾
14 CLINICAL STUDIES
14.1Effects on Vasomotor Symptoms In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups of either placebo or CE, with or without MPA. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization.
With PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg, the relief of both the frequency and severity of moderate to severe vasomotor symptoms was shown to be statistically improved compared to placebo at weeks 4 and 12. Table 5 shows the adjusted mean number of hot flushes in the PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, 0.3 mg/1.5 mg, and placebo groups during the initial 12-week period. Table 5: Summary Tabulation of the Number of Hot Flushes Per Day – Mean Values and Comparisons Between the Active Treatment Groups and the Placebo Group – Patients with At Least 7 Moderate to Severe Flushes Per Day or At Least 50 Per Week at Baseline, Last Observation Carries Forward (LOCF) Treatment Identified by dosage (mg) of Premarin/MPA or placebo.
(No. of Patients) -------------------No. of Hot Flushes/Day----------------- Time Period (week) Baseline Mean ± SD Observed Mean ± SD Mean Change ± SD p-Values vs. Placebo There were no statistically significant differences between the 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg groups at any time period. 0.625 mg/2.5 mg (n = 34) 4 11.98 ± 3.54 3.19 ± 3.74 -8.78 ± 4.72 <0.001 12 11.98 ± 3.54 1.16 ± 2.22 -10.82 ± 4.61 <0.001 0.45 mg/1.5 mg (n = 29) 4 12.61 ± 4.29 3.64 ± 3.61 -8.98 ± 4.74 <0.001 12 12.61 ± 4.29 1.69 ± 3.36 -10.92 ± 4.63 <0.001 0.3 mg/1.5 mg (n = 33) 4 11.30 ± 3.13 3.70 ± 3.29 -7.60 ± 4.71 <0.001 12 11.30 ± 3.13 1.31 ± 2.82 -10.00 ± 4.60 <0.001 Placebo (n = 28) 4 11.69 ± 3.87 7.89 ± 5.28 -3.80 ± 4.71 - 12 11.69 ± 3.87 5.71 ± 5.22 -5.98 ± 4.60 -
14.2Effects on Vulvar and Vaginal Atrophy Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p < 0.001) for all treatment groups.
14.3Effects on the Endometrium In a 1-year clinical trial of 1,376 women (average age 54 ± 4.6 years) randomized to PREMPRO 0.625 mg/2.5 mg (n = 340), PREMPRO 0.625 mg/5 mg (n = 338), PREMPHASE 0.625 mg/5 mg (n = 351), or Premarin 0.625 mg alone (n = 347), results of evaluable biopsies at 12 months (n = 279, 274, 277, and 283, respectively) showed a reduced risk of endometrial hyperplasia in the two PREMPRO treatment groups (less than 1%) and in the PREMPHASE treatment group (less than 1%; 1% when focal hyperplasia was included) compared to the Premarin group (8%; 20% when focal hyperplasia was included), see Table 6 .
Table 6: Incidence of Endometrial Hyperplasia After One Year of Treatment --------------------------Groups------------------------- PREMPRO PREMPRO PREMPHASE Premarin 0.625 mg/2.5 mg 0.625 mg/5 mg 0.625 mg/5 mg 0.625 mg Total number of patients 340 338 351 347 Number of patients with evaluable biopsies 279 274 277 283 No. (%) of patients with biopsies: • All focal and non-focal hyperplasia 2 (<1) Significant (p < 0.001) in comparison with Premarin (0.625 mg) alone. 0 (0) 3 (1) 57 (20) • Excluding focal cystic hyperplasia 2 (<1) 0 (0) 1 (<1) 25 (8) In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 2,001 women (average age 53.3 ± 4.9 years), of whom 88% were Caucasian, were treated with either Premarin 0.625 mg alone (n = 348), Premarin 0.45 mg alone (n = 338), Premarin 0.3 mg alone (n = 326) or PREMPRO 0.625 mg/2.5 mg (n = 331), PREMPRO 0.45 mg/1.5 mg (n = 331) or PREMPRO 0.3 mg/1.5 mg (n = 327).
Results of evaluable endometrial biopsies at 12 months showed a reduced risk of endometrial hyperp… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breasts, uterus, cervix, vagina, testis, and liver [see Warnings and Precautions (5.2) ] . MPA was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays [see Warnings and Precautions (5.7) ] .
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breasts, uterus, cervix, vagina, testis, and liver [see Warnings and Precautions (5.2) ] . MPA was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays [see Warnings and Precautions (5.7) ] .
📚 References ▾
15 REFERENCES 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause.
JAMA . 2007;297:1465–1477. 2.
Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med.
2006;166:357–365. 3. Cushman M, et al.
Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA . 2004;292:1573–1580.
4. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus.
Arch Int Med . 2006;166:772–780. 5.
Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA .
2006;295:1647-1657. 6. Chlebowski RT, et al.
Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA . 2003;289:3234–3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures.
JAMA . 2003;290:1739–1748. 8.
Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA .
2004;291:2947–2958. 9. Jackson RD, et al.
Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res . 2006;21:817–828.
10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative.
Circulation . 2006;113:2425–2434.
📄 Patient Package Insert ▾
PATIENT INFORMATION PREMPRO ® (Conjugated Estrogens/Medroxyprogesterone Acetate Tablets) PREMPHASE ® (Conjugated Estrogens plus Medroxyprogesterone Acetate Tablets) Read this PATIENT INFORMATION before you start taking PREMPRO or PREMPHASE and read what you get each time you refill your PREMPRO or PREMPHASE 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 PREMPRO and PREMPHASE (combinations of estrogens and a progestin)? • Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function) • 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 • Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia • Using estrogen-alone may increase your chance of getting cancer of the uterus (womb) • 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 • You and your healthcare provider should talk regularly about whether you still need treatment with PREMPRO or PREMPHASE What is PREMPRO or PREMPHASE?
PREMPRO or PREMPHASE are medicines that contain two kinds of hormones, estrogens and a progestin. What is PREMPRO or PREMPHASE used for? PREMPRO or PREMPHASE is used after menopause to: • Reduce moderate to severe hot flushes Estrogens are hormones made by a woman's ovaries.
The ovaries normally stop making estrogens when a woman is between 45 and 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 get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("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 PREMPRO or PREMPHASE to control these problems.
If you use PREMPRO or PREMPHASE 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 PREMPRO or PREMPHASE 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 PREMPRO or PREMPHASE.
Who should not take PREMPRO or PREMPHASE? Do not take PREMPRO or PREMPHASE if you have had your uterus (womb) removed (hysterectomy). PREMPRO and PREMPHASE contain a progestin to decrease the chance of getting cancer of the uterus.
If you do not have a uterus, you do not need a progestin a… [Excerpted — this section continues on DailyMed.]
📄 Package Label / Principal Display Panel ▾
PRINCIPAL DISPLAY PANEL - 28 Tablet 0.625 mg / 5 mg Blister Pack START HERE Rx only NDC 0046-2575-12 DAY 1 → DAY 2 → DAY 3 → DAY 4 → DAY 5 → DAY 6 → DAY 7 14 maroon tablets of 0.625 mg conjugated estrogens DAY 14 ← DAY 13 ← DAY 12 ← DAY 11 ← DAY 10 ← DAY 9 ← DAY 8 PREMPHASE ® (conjugated estrogens/medroxyprogesterone acetate tablets) DAY 15 → DAY 16 → DAY 17 → DAY 18 → DAY 19 → DAY 20 → DAY 21 14 light-blue tablets of 0.625 mg conjugated estrogens/5 mg medroxyprogesterone acetate DAY 28 ← DAY 27 ← DAY 26 ← DAY 25 ← DAY 24 ← DAY 23 ← DAY 22 PRINCIPAL DISPLAY PANEL - 28 Tablet 0.625 mg / 5 mg Blister Pack
PRINCIPAL DISPLAY PANEL - Kit Carton NDC 0046-2575-12 Pfizer PREMPHASE ® (conjugated estrogens/medroxyprogesterone acetate tablets) 14 maroon tablets of 0.625 mg conjugated estrogens 14 light-blue tablets of 0.625 mg conjugated estrogens/ 5 mg medroxyprogesterone acetate Package contains 1 blister card of 28 tablets Rx only PRINCIPAL DISPLAY PANEL - Kit Carton
PRINCIPAL DISPLAY PANEL - 0.3 mg / 1.5 mg Blister Card 28 Tablets NDC 0046-1105-11 WEEK 1 WEEK 2 WEEK 3 WEEK 4 Pfizer PREMPRO ® (conjugated estrogens/medroxyprogesterone acetate tablets) 0.3 mg / 1.5 mg Each cream tablet contains 0.3 mg of Premarin ® brand of conjugated estrogens and 1.5 mg of medroxyprogesterone acetate. Directions for Use: Take one tablet each day until all tablets have been taken. See accompanying information.
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] Note: Package not child resistant. Keep this and all medications out of the reach of children. PREMPRO 0.3 mg/1.5 mg Distributed by Wyeth Pharmaceuticals LLC A subsidiary of Pfizer Inc.
Philadelphia, PA 19101 www.PREMPRO.com Rx only PAA224096 WEEK 1 WEEK 2 WEEK 3 WEEK 4 LOT XXXXXXX EXP YYYY-MMM PRINCIPAL DISPLAY PANEL - 0.3 mg / 1.5 mg Blister Card
PRINCIPAL DISPLAY PANEL - 0.3 mg / 1.5 mg Blister Card Carton NDC 0046-1105-11 Pfizer PREMPRO ® (conjugated estrogens/ medroxyprogesterone acetate tablets) 0.3 mg / 1.5 mg Package contains 1 blister card of 28 tablets. www.PREMPRO.com Rx only PRINCIPAL DISPLAY PANEL - 0.3 mg / 1.5 mg Blister Card Carton
PRINCIPAL DISPLAY PANEL - 0.45 mg / 1.5 mg Blister Card 28 Tablets NDC 0046-1106-11 WEEK 1 WEEK 2 WEEK 3 WEEK 4 Pfizer PREMPRO ® (conjugated estrogens/medroxyprogesterone acetate tablets) 0.45 mg / 1.5 mg Each gold tablet contains 0.45 mg of Premarin ® brand of conjugated estrogens and 1.5 mg of medroxyprogesterone acetate. Directions for Use: Take one tablet each day until all tablets have been taken. See accompanying information.
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] Note: Package not child resistant. Keep this and all medications out of the reach of children. PREMPRO 0.45 mg/1.5 mg Distributed by Wyeth Pharmaceuticals LLC A subsidiary of Pfizer Inc.
Philadelphia, PA 19101 www.PREMPRO.com Rx only PAA224094 WEEK 1 WEEK 2 WEEK 3 WEEK 4 LOT XXXXXXX EXP YYYY-MMM PRINCIPAL DISPLAY PANEL - 0.45 mg / 1.5 mg Blister Card
PRINCIPAL DISPLAY PANEL - 0.45 mg / 1.5 mg Blister Card Carton NDC 0046-1106-11 Pfizer PREMPRO ® (conjugated estrogens/ medroxyprogesterone acetate tablets) 0.45 mg / 1.5 mg Package contains 1 blister card of 28 tablets. www.PREMPRO.com Rx only PRINCIPAL DISPLAY PANEL - 0.45 mg / 1.5 mg Blister Card Carton
PRINCIPAL DISPLAY PANEL - 0.625 mg / 2.5 mg Tablet Blister Card 28 Tablets NDC 0046-1107-11 WEEK 1 WEEK 2 WEEK 3 WEEK 4 Pfizer PREMPRO ® (conjugated estrogens/medroxyprogesterone acetate tablets) 0.625 mg / 2.5 mg Each peach tablet contains 0.625 mg of Premarin ® brand of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate. Directions for Use: Take one tablet each day until all tablets have been taken. See accompanying information.
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] Note: Packa… [Excerpted — this section continues on DailyMed.]