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Conjugated Estrogens And Medroxyprogesterone Acetate

FDA Drug Information • Also known as: Premphase, Prempro

Brand Names
Premphase, Prempro
Drug Class
Estrogen [EPC]
Dosage Form
KIT
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.6 , 14.7) ] . The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) (0.625 mg) combined with medroxyprogesterone acetate (MPA) (2.5 mg), relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.6) ] . The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.7) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2) , and Clinical Studies (14.6) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.6 , 14.7) ] . The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1) , and Clinical Studies (14.6) ] . The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.7) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA See full prescribing information for complete boxed warning. Estrogen Plus Progestin Therapy

  • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 )
  • The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) ( 5.1 )
  • The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.2 )
  • The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Estrogen-Alone Therapy
  • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 )
  • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 )
  • The WHI estrogen-alone substudy reported increased risks of stroke and DVT ( 5.1 )
  • The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 )

    • 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...

    What Is Conjugated Estrogens And Medroxyprogesterone Acetate 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 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 ) 2.1 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.

    Side Effects (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 . 6.1 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...

    • 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 ) 7.1 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.

    • 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 )

    • Pregnancy and Breastfeeding

    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.

    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.

    How Supplied

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

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.