Prempro

— THERAPEUTIC CATEGORIES —
  • Bone disorders
  • Menopause and HRT
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Prempro Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Conjugated estrogens, medroxyprogesterone acetate; 0.3mg/1.5mg, 0.45mg/1.5mg, 0.625mg/2.5mg, 0.625mg/5mg; tabs.

    Pharmacological Class

    Estrogen + progestin.

    How Supplied

    Blister card (28 tabs)—1

    How Supplied

    Prempro 0.3mg/1.5mg:

    • supplied as a carton that includes 1 blister card containing 28 oval, cream tablets. 

    Prempro 0.45mg/1.5mg: 

    • supplied as a carton that includes 1 blister card containing 28 oval, gold tablets.

    Prempro 0.625mg/2.5mg:

    • supplied as a carton that includes 1 blister card containing 28 oval, peach tablets. 

    Prempro 0.625mg/5mg: 

    • supplied as a carton that includes 1 blister card containing 28 oval, light-blue tablets.

    Storage

    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].

    Manufacturer

    Pfizer Inc.

    Mechanism of Action

    Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. 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. 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.

    Prempro Indications

    Indications

    Prevention of postmenopausal osteoporosis.

    Prempro Dosage and Administration

    Adult

    1 tab once daily.

    Children

    Not applicable.

    Prempro Contraindications

    Contraindications

    Undiagnosed abnormal genital bleeding. Breast or other estrogen-dependent neoplasms. Active DVT, PE, or history of. Active arterial thromboembolic disease (eg, stroke, MI) or a history of. Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Pregnancy.

    Prempro Boxed Warnings

    Boxed Warning

    Endometrial cancer. Breast cancer. Cardiovascular disorders. Probable dementia.

    Boxed Warning

    Estrogen Plus Progestin Therapy

    • Cardiovascular disorders and Probable Dementia

      • Do not use estrogen plus progestin therapy for the prevention of cardiovascular disease or dementia. 

      • According to the Women’s Health Initiative (WHI) estrogen plus progestin substudy, there is an increased risk for DVT, PE, stroke, and MI in postmenopausal women 50 to 79 years of age during 5.6 years of treatment with daily oral conjugated estrogen (CE) 0.625mg combined with medroxyprogesterone acetate (MPA) 2.5mg compared with placebo.

      • According to the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, there is an increased risk for developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE 0.625mg combined with MPA 2.5mg compared with placebo. It is unknown if these findings are applicable to younger postmenopausal women.

    • Breast Cancer

      • According to the WHI estrogen plus progestin substudy, there is an increased risk for invasive breast cancer.

      • Prescribe estrogens with or without progestins 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 for endometrial cancer in a woman with a uterus who uses unopposed estrogens. The addition of progestin to estrogen therapy has shown to reduce the risk for endometrial hyperplasia.

      • Obtain adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

    • Cardiovascular disorders and Probable Dementia

      • Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia.

      • According to the Women’s Health Initiative (WHI) estrogen-alone substudy, there is an increased risk for DVT and stroke in postmenopausal women 50 to 79 years of age during 7.1 years of treatment with daily oral CE 0.625mg alone compared with placebo.

      • According to the WHI Memory Study (WHIMS) estrogen-alone ancillary study, there is an increased risk for developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE 0.625mg-alone compared with placebo. It is unknown if these findings are applicable to younger postmenopausal women.

      • Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

    Prempro Warnings/Precautions

    Warnings/Precautions

    Increased risk of endometrial carcinoma or hyperplasia in women with intact uterus (adding progestin is essential). Not for prevention of cardiovascular disease or dementia. Increased risk of cardiovascular events (eg, MI, stroke, VTE); discontinue if occurs. Manage risk factors for cardiovascular disease and venous thromboembolism appropriately. Discontinue at least 4–6 weeks before surgery type associated with increased risk of thromboembolism or during prolonged immobilization. Increased risk of breast or ovarian cancer. Risk of probable dementia in women >65yrs of age. Gallbladder disease. Severe hypercalcemia in breast cancer or bone metastases. Visual abnormalities. Permanently discontinue if papilledema or retinal vascular lesions reveals on exam. Preexisting hypertriglyceridemia. History of cholestatic jaundice. Discontinue if pancreatitis, hypercalcemia, or recurrence of cholestatic jaundice occurs. Monitor thyroid function. Conditions aggravated by fluid retention. Hypoparathyroidism. Endometriosis. Hereditary angioedema. Asthma. Diabetes. Epilepsy. Migraine. Porphyria. SLE. Hepatic hemangiomas. Do initial complete physical and repeat annually (include Pap smear, mammogram, and BP). Reevaluate periodically. Nursing mothers: not recommended.

    Warnings/Precautions

    Cardiovascular Disorders 

    • Increased risk for PE, DVT, stroke, and MI with estrogen plus progestin therapy. Increased risk for stroke and DVT with estrogen-alone therapy. Immediately discontinue estrogen with or without progestin therapy if any of these occur or be suspected.

    • Manage appropriately in patients with risk factors for arterial vascular disease (eg, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (eg, personal history or family history of VTE, obesity, and systemic lupus erythematosus).

    • Discontinue estrogen plus progestin or estrogen-alone therapy immediately if VTE or stroke occurs or be suspected. 

    • If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

    Malignant Neoplasms

    • Breast Cancer: According to the WHI clinical trials, observational studies have also reported an increased risk for breast cancer with estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy after several years of use. There is an increase in abnormal mammograms requiring further evaluation associated with the use of estrogen-alone and estrogen plus progestin therapy. Advise all women to receive yearly breast exams and perform monthly breast self-exams.

    • Endometrial Cancer: Reports have shown that there is an increased risk for endometrial cancer with the use of unopposed estrogen therapy in a woman with a uterus. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. Initiate adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

    • Ovarian Cancer: Reports have shown that there is a statistically nonsignificant increased risk for ovarian cancer. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

    Probable Dementia

    • After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone vs placebo was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone vs placebo was 37 vs 25 cases per 10,000 women-years.

    • When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

    Gallbladder Disease

    • There is a 2- to 4-fold increase in the risk for gallbladder disease requiring surgery in postmenopausal women receiving estrogens.

    Hypercalcemia

    • Risk for severe hypercalcemia when administering estrogen in women with breast cancer and bone metastases.

    • Discontinue drug if hypercalcemia occurs and take appropriate measures to reduce the serum calcium level.

    Visual Abnormalities

    • Women receiving estrogens have reported retinal vascular thrombosis. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens if examination reveals papilledema or retinal vascular lesions.

    Addition of a Progestin When a Woman has not had a Hysterectomy

    • According to studies, a lowered incidence of endometrial hyperplasia has been reported when progestin was added for 10 or more days of a cycle of estrogen administration or daily with estrogen vs when induced by estrogen treatment alone. However, the use of progestin with estrogen may be associated with an increased risk for breast cancer.

    Elevated Blood Pressure

    • A small number of case reports have reported a substantial increase in blood pressure attributed to idiosyncratic reactions to estrogens.

    Hypertriglyceridemia

    • There may be an increased risk for elevated plasma triglycerides leading to pancreatitis when administering estrogen therapy to women with pre-existing hypertriglyceridemia. Consider discontinuing treatment if pancreatitis occurs.

    Hepatic Impairment and/or Past History of Cholestatic Jaundice 

    • Women with hepatic impairment may poorly metabolize estrogens. Exercise caution, and in the case of recurrence, discontinue estrogen in women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy.

    Hypothyroidism

    • Estrogen therapy leads to increased thyroid-binding globulin (TBG) levels.

    • Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

    Fluid Retention

    • Estrogens plus progestins may cause some degree of fluid retention.

    • When prescribing estrogens plus progestins, carefully monitor women with conditions that may be affected by fluid retention, such as cardiac or renal dysfunction.

    Hypocalcemia

    • Exercise caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

    Exacerbation of Endometriosis

    • A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. 

    • Consider adding progestin for women known to have residual endometriosis post-hysterectomy.

    Anaphylactic Reaction and Angioedema

    • Cases of anaphylaxis, which developed within minutes to hours after taking Prempro or Premphase and require emergency medical management, have been reported in the postmarketing setting.

    • Do not administer Prempro or Premphase again to patients who develop an anaphylactic reaction with or without angioedema after treatment with Prempro or Premphase.

    Hereditary Angioedema

    • Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

    Exacerbation of Other Conditions

    • Use caution in patients with asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas.

    Laboratory Tests

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

    Drug-Laboratory Test Interactions

    • May interfere with lab tests (eg, thyroid, PT, coagulation factors, glucose tolerance, HDL/LDL, triglycerides, hormone concentrations, other binding or plasma proteins).

    Pregnancy Considerations

    Do not use during pregnancy. There is little to no increased risk for birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

     

    Nursing Mother Considerations

    Do not use during lactation. Estrogen therapy has been shown to decrease the quantity and quality of the breast milk. Exercise caution when administering Prempro or Premphase to a nursing woman.

     

    Renal Impairment Considerations

    The effects of renal impairment on the pharmacokinetics of Prempro or Premphase have not been studied.

    Hepatic Impairment Considerations

    The effects of hepatic impairment on the pharmacokinetics of Prempro or Premphase have not been studied.

    Prempro Pharmacokinetics

    Distribution

    Estrogens circulate in the blood largely bound to SHBG and albumin. MPA is ~90% bound to plasma proteins, but does not bind to SHBG.

    Metabolism

    Estrogens are metabolized mainly in the liver. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption.

    Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

    Elimination

    Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates, with only minor amounts excreted as sulfates. 

    Prempro Interactions

    Interactions

    May be potentiated by CYP3A4 inhibitors (eg, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, grapefruit juice). May be antagonized by CYP3A4 inducers (eg, phenobarbital, carbamazepine, rifampin, St. John’s wort). Concomitant thyroid replacement; may need to increase thyroid dose. Concomitant aminoglutethimide: may reduce bioavailability of medroxyprogesterone. May interfere with lab tests (eg, thyroid, PT, coagulation factors, glucose tolerance, HDL/LDL, triglycerides, hormone concentrations, other binding or plasma proteins).

    Prempro Adverse Reactions

    Adverse Reactions

    Abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, leukorrhea; thromboembolism, neoplasms, anaphylaxis, angioedema (permanently discontinue if occurs).

    Prempro Clinical Trials

    Clinical Trials

    Effects on Vasomotor Symptoms 

    • The Health and Osteoporosis, Progestin and Estrogen (HOPE) Study compared conjugated estrogens to placebo in 2805 postmenopausal women (mean age 53.3 ± 4.9 years). Patients were randomly assigned to receive 1 of 8 treatment groups of either placebo or conjugated estrogens, with or without medroxyprogesterone acetate.

    • 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 7 moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization.

    • The relief of both the frequency and severity of moderate to severe vasomotor symptoms was shown to be statistically improved with Prempro 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg vs placebo at weeks 4 and 12.

    Effects 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 <.001) for all treatment groups.

    Effects on the Endometrium

    • A 1-year clinical trial compared 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) in a total of 1,376 women (average age 54 ± 4.6 years).

    • At 12 months, results of evaluable biopsies 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).

    • In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2001 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 showed there was a reduced risk of endometrial hyperplasia or cancer in the Prempro treatment groups among evaluable endometrial biopsies at 12 months vs the Premarin alone treatment groups, except for the Prempro 0.3 mg/1.5 mg and Premarin 0.3 mg alone groups.

    Effects on Bone Mineral Density

    • The HOPE study evaluated healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ± 0.9 years on average since menopause and took one 600 mg tablet of elemental calcium (Caltrate™) daily. Subjects were treated with Prempro 0.625 mg/2.5 mg, 0.45 mg/1.5 mg or 0.3 mg/1.5 mg, comparable doses of Premarin alone, or placebo. Subjects were not given Vitamin D supplements. 

    • All active treatment groups showed significant differences from placebo in each of the four BMD endpoints, including measurement of BMD at L2 to L4, total body, femoral neck, and trochanter. Significant differences between each of the Prempro dosage groups and placebo were found at cycles 6, 13, 19, and 26.

    • All active-treatment groups also showed significant decreases in bone turnover markers, serum osteocalcin and urinary N-telopeptide (P <.001) at cycles 6, 13, 19, and 26 vs the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium; only with Prempro 0.625 mg/2.5 mg and 0.45 mg/1.5 mg were there significantly larger mean decreases than with placebo at 3 or more of the 4 time points.

     

    Women’s Health Initiative Studies

    Women’s Health Initiative (WHI) Estrogen Plus Progestin Substudy

    • The WHI estrogen plus progestin substudy was stopped early due to an increased risk for invasive breast cancer and cardiovascular events that exceeded the specified benefits included in the “global index”.

    • The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95% CI, 0.44-1.07)].

    WHI Estrogen-Alone Substudy

    • The WHI estrogen plus progestin substudy was stopped early due to an increased risk for stroke. For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.  

    Women’s Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study

    • The study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were 65 to 69 years of age; 35% were 70 to 74 years of age; and 18% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. 

    • After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA vs placebo was 2.05 (95% CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA vs placebo was 45 vs 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD).

    WHIMS estrogen-alone ancillary study

    • The study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45% were 65 to 69 years of age; 36% were 70 to 74 years of age; 19% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

    • After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone vs placebo was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone vs placebo was 37 vs 25 cases per 10,000 women-years.

    • When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women.

    Prempro Note

    Not Applicable

    Prempro Patient Counseling

    Patient Counseling

    Abnormal Vaginal Bleeding

    • Advise postmenopausal women to report abnormal vaginal bleed to their healthcare provider as soon as possible.

    Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy

    • Advise postmenopausal women of the risks for serious adverse reactions of estrogen plus progestin therapy including cardiovascular disorders, malignant neoplasms, and probable dementia.

    Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy

    • Advise postmenopausal women of the risk for less serious but common adverse reactions of estrogen plus progestin therapy (eg, headache, breast pain and tenderness, nausea and vomiting).

    Prempro Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Conjugated estrogens, medroxyprogesterone acetate; 0.3mg/1.5mg, 0.45mg/1.5mg, 0.625mg/2.5mg, 0.625mg/5mg; tabs.

    Pharmacological Class

    Estrogen + progestin.

    How Supplied

    Blister card (28 tabs)—1

    How Supplied

    Prempro 0.3mg/1.5mg:

    • supplied as a carton that includes 1 blister card containing 28 oval, cream tablets. 

    Prempro 0.45mg/1.5mg: 

    • supplied as a carton that includes 1 blister card containing 28 oval, gold tablets.

    Prempro 0.625mg/2.5mg:

    • supplied as a carton that includes 1 blister card containing 28 oval, peach tablets. 

    Prempro 0.625mg/5mg: 

    • supplied as a carton that includes 1 blister card containing 28 oval, light-blue tablets.

    Storage

    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].

    Manufacturer

    Pfizer Inc.

    Mechanism of Action

    Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. 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. 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.

    Prempro Indications

    Indications

    Moderate to severe vasomotor symptoms of menopause. Moderate to severe vulvar and vaginal atrophy due to menopause. 

    Prempro Dosage and Administration

    Adult

    1 tab once daily.

    Children

    Not applicable.

    Prempro Contraindications

    Contraindications

    Undiagnosed abnormal genital bleeding. Breast or other estrogen-dependent neoplasms. Active DVT, PE, or history of. Active arterial thromboembolic disease (eg, stroke, MI) or a history of. Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Pregnancy.

    Prempro Boxed Warnings

    Boxed Warning

    Endometrial cancer. Breast cancer. Cardiovascular disorders. Probable dementia.

    Boxed Warning

    Estrogen Plus Progestin Therapy

    • Cardiovascular disorders and Probable Dementia

      • Do not use estrogen plus progestin therapy for the prevention of cardiovascular disease or dementia. 

      • According to the Women’s Health Initiative (WHI) estrogen plus progestin substudy, there is an increased risk for DVT, PE, stroke, and MI in postmenopausal women 50 to 79 years of age during 5.6 years of treatment with daily oral conjugated estrogen (CE) 0.625mg combined with medroxyprogesterone acetate (MPA) 2.5mg compared with placebo.

      • According to the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, there is an increased risk for developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE 0.625mg combined with MPA 2.5mg compared with placebo. It is unknown if these findings are applicable to younger postmenopausal women.

    • Breast Cancer

      • According to the WHI estrogen plus progestin substudy, there is an increased risk for invasive breast cancer.

      • Prescribe estrogens with or without progestins 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 for endometrial cancer in a woman with a uterus who uses unopposed estrogens. The addition of progestin to estrogen therapy has shown to reduce the risk for endometrial hyperplasia.

      • Obtain adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

    • Cardiovascular disorders and Probable Dementia

      • Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia.

      • According to the Women’s Health Initiative (WHI) estrogen-alone substudy, there is an increased risk for DVT and stroke in postmenopausal women 50 to 79 years of age during 7.1 years of treatment with daily oral CE 0.625mg alone compared with placebo.

      • According to the WHI Memory Study (WHIMS) estrogen-alone ancillary study, there is an increased risk for developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE 0.625mg-alone compared with placebo. It is unknown if these findings are applicable to younger postmenopausal women.

      • Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

    Prempro Warnings/Precautions

    Warnings/Precautions

    Increased risk of endometrial carcinoma or hyperplasia in women with intact uterus (adding progestin is essential). Not for prevention of cardiovascular disease or dementia. Increased risk of cardiovascular events (eg, MI, stroke, VTE); discontinue if occurs. Manage risk factors for cardiovascular disease and venous thromboembolism appropriately. Discontinue at least 4–6 weeks before surgery type associated with increased risk of thromboembolism or during prolonged immobilization. Increased risk of breast or ovarian cancer. Risk of probable dementia in women >65yrs of age. Gallbladder disease. Severe hypercalcemia in breast cancer or bone metastases. Visual abnormalities. Permanently discontinue if papilledema or retinal vascular lesions reveals on exam. Preexisting hypertriglyceridemia. History of cholestatic jaundice. Discontinue if pancreatitis, hypercalcemia, or recurrence of cholestatic jaundice occurs. Monitor thyroid function. Conditions aggravated by fluid retention. Hypoparathyroidism. Endometriosis. Hereditary angioedema. Asthma. Diabetes. Epilepsy. Migraine. Porphyria. SLE. Hepatic hemangiomas. Do initial complete physical and repeat annually (include Pap smear, mammogram, and BP). Reevaluate periodically. Nursing mothers: not recommended.

    Warnings/Precautions

    Cardiovascular Disorders 

    • Increased risk for PE, DVT, stroke, and MI with estrogen plus progestin therapy. Increased risk for stroke and DVT with estrogen-alone therapy. Immediately discontinue estrogen with or without progestin therapy if any of these occur or be suspected.

    • Manage appropriately in patients with risk factors for arterial vascular disease (eg, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (eg, personal history or family history of VTE, obesity, and systemic lupus erythematosus).

    • Discontinue estrogen plus progestin or estrogen-alone therapy immediately if VTE or stroke occurs or be suspected. 

    • If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

    Malignant Neoplasms

    • Breast Cancer: According to the WHI clinical trials, observational studies have also reported an increased risk for breast cancer with estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy after several years of use. There is an increase in abnormal mammograms requiring further evaluation associated with the use of estrogen-alone and estrogen plus progestin therapy. Advise all women to receive yearly breast exams and perform monthly breast self-exams.

    • Endometrial Cancer: Reports have shown that there is an increased risk for endometrial cancer with the use of unopposed estrogen therapy in a woman with a uterus. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. Initiate adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

    • Ovarian Cancer: Reports have shown that there is a statistically nonsignificant increased risk for ovarian cancer. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

    Probable Dementia

    • After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone vs placebo was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone vs placebo was 37 vs 25 cases per 10,000 women-years.

    • When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

    Gallbladder Disease

    • There is a 2- to 4-fold increase in the risk for gallbladder disease requiring surgery in postmenopausal women receiving estrogens.

    Hypercalcemia

    • Risk for severe hypercalcemia when administering estrogen in women with breast cancer and bone metastases.

    • Discontinue drug if hypercalcemia occurs and take appropriate measures to reduce the serum calcium level.

    Visual Abnormalities

    • Women receiving estrogens have reported retinal vascular thrombosis. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens if examination reveals papilledema or retinal vascular lesions.

    Addition of a Progestin When a Woman has not had a Hysterectomy

    • According to studies, a lowered incidence of endometrial hyperplasia has been reported when progestin was added for 10 or more days of a cycle of estrogen administration or daily with estrogen vs when induced by estrogen treatment alone. However, the use of progestin with estrogen may be associated with an increased risk for breast cancer.

    Elevated Blood Pressure

    • A small number of case reports have reported a substantial increase in blood pressure attributed to idiosyncratic reactions to estrogens.

    Hypertriglyceridemia

    • There may be an increased risk for elevated plasma triglycerides leading to pancreatitis when administering estrogen therapy to women with pre-existing hypertriglyceridemia. Consider discontinuing treatment if pancreatitis occurs.

    Hepatic Impairment and/or Past History of Cholestatic Jaundice 

    • Women with hepatic impairment may poorly metabolize estrogens. Exercise caution, and in the case of recurrence, discontinue estrogen in women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy.

    Hypothyroidism

    • Estrogen therapy leads to increased thyroid-binding globulin (TBG) levels.

    • Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

    Fluid Retention

    • Estrogens plus progestins may cause some degree of fluid retention.

    • When prescribing estrogens plus progestins, carefully monitor women with conditions that may be affected by fluid retention, such as cardiac or renal dysfunction.

    Hypocalcemia

    • Exercise caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

    Exacerbation of Endometriosis

    • A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. 

    • Consider adding progestin for women known to have residual endometriosis post-hysterectomy.

    Anaphylactic Reaction and Angioedema

    • Cases of anaphylaxis, which developed within minutes to hours after taking Prempro or Premphase and require emergency medical management, have been reported in the postmarketing setting.

    • Do not administer Prempro or Premphase again to patients who develop an anaphylactic reaction with or without angioedema after treatment with Prempro or Premphase.

    Hereditary Angioedema

    • Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

    Exacerbation of Other Conditions

    • Use caution in patients with asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas.

    Laboratory Tests

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

    Drug-Laboratory Test Interactions

    • May interfere with lab tests (eg, thyroid, PT, coagulation factors, glucose tolerance, HDL/LDL, triglycerides, hormone concentrations, other binding or plasma proteins).

    Pregnancy Considerations

    Do not use during pregnancy. There is little to no increased risk for birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

     

    Nursing Mother Considerations

    Do not use during lactation. Estrogen therapy has been shown to decrease the quantity and quality of the breast milk. Exercise caution when administering Prempro or Premphase to a nursing woman.

     

    Renal Impairment Considerations

    The effects of renal impairment on the pharmacokinetics of Prempro or Premphase have not been studied.

    Hepatic Impairment Considerations

    The effects of hepatic impairment on the pharmacokinetics of Prempro or Premphase have not been studied.

    Prempro Pharmacokinetics

    Distribution

    Estrogens circulate in the blood largely bound to SHBG and albumin. MPA is ~90% bound to plasma proteins, but does not bind to SHBG.

    Metabolism

    Estrogens are metabolized mainly in the liver. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption.

    Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

    Elimination

    Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates, with only minor amounts excreted as sulfates. 

    Prempro Interactions

    Interactions

    May be potentiated by CYP3A4 inhibitors (eg, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, grapefruit juice). May be antagonized by CYP3A4 inducers (eg, phenobarbital, carbamazepine, rifampin, St. John’s wort). Concomitant thyroid replacement; may need to increase thyroid dose. Concomitant aminoglutethimide: may reduce bioavailability of medroxyprogesterone. May interfere with lab tests (eg, thyroid, PT, coagulation factors, glucose tolerance, HDL/LDL, triglycerides, hormone concentrations, other binding or plasma proteins).

    Prempro Adverse Reactions

    Adverse Reactions

    Abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, leukorrhea; thromboembolism, neoplasms, anaphylaxis, angioedema (permanently discontinue if occurs).

    Prempro Clinical Trials

    Clinical Trials

    Effects on Vasomotor Symptoms 

    • The Health and Osteoporosis, Progestin and Estrogen (HOPE) Study compared conjugated estrogens to placebo in 2805 postmenopausal women (mean age 53.3 ± 4.9 years). Patients were randomly assigned to receive 1 of 8 treatment groups of either placebo or conjugated estrogens, with or without medroxyprogesterone acetate.

    • 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 7 moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization.

    • The relief of both the frequency and severity of moderate to severe vasomotor symptoms was shown to be statistically improved with Prempro 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg vs placebo at weeks 4 and 12.

    Effects 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 <.001) for all treatment groups.

    Effects on the Endometrium

    • A 1-year clinical trial compared 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) in a total of 1,376 women (average age 54 ± 4.6 years).

    • At 12 months, results of evaluable biopsies 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).

    • In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2001 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 showed there was a reduced risk of endometrial hyperplasia or cancer in the Prempro treatment groups among evaluable endometrial biopsies at 12 months vs the Premarin alone treatment groups, except for the Prempro 0.3 mg/1.5 mg and Premarin 0.3 mg alone groups.

    Effects on Bone Mineral Density

    • The HOPE study evaluated healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ± 0.9 years on average since menopause and took one 600 mg tablet of elemental calcium (Caltrate™) daily. Subjects were treated with Prempro 0.625 mg/2.5 mg, 0.45 mg/1.5 mg or 0.3 mg/1.5 mg, comparable doses of Premarin alone, or placebo. Subjects were not given Vitamin D supplements. 

    • All active treatment groups showed significant differences from placebo in each of the four BMD endpoints, including measurement of BMD at L2 to L4, total body, femoral neck, and trochanter. Significant differences between each of the Prempro dosage groups and placebo were found at cycles 6, 13, 19, and 26.

    • All active-treatment groups also showed significant decreases in bone turnover markers, serum osteocalcin and urinary N-telopeptide (P <.001) at cycles 6, 13, 19, and 26 vs the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium; only with Prempro 0.625 mg/2.5 mg and 0.45 mg/1.5 mg were there significantly larger mean decreases than with placebo at 3 or more of the 4 time points.

     

    Women’s Health Initiative Studies

    Women’s Health Initiative (WHI) Estrogen Plus Progestin Substudy

    • The WHI estrogen plus progestin substudy was stopped early due to an increased risk for invasive breast cancer and cardiovascular events that exceeded the specified benefits included in the “global index”.

    • The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95% CI, 0.44-1.07)].

    WHI Estrogen-Alone Substudy

    • The WHI estrogen plus progestin substudy was stopped early due to an increased risk for stroke. For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.  

    Women’s Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study

    • The study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were 65 to 69 years of age; 35% were 70 to 74 years of age; and 18% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. 

    • After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA vs placebo was 2.05 (95% CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA vs placebo was 45 vs 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD).

    WHIMS estrogen-alone ancillary study

    • The study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45% were 65 to 69 years of age; 36% were 70 to 74 years of age; 19% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

    • After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone vs placebo was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone vs placebo was 37 vs 25 cases per 10,000 women-years.

    • When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women.

    Prempro Note

    Not Applicable

    Prempro Patient Counseling

    Patient Counseling

    Abnormal Vaginal Bleeding

    • Advise postmenopausal women to report abnormal vaginal bleed to their healthcare provider as soon as possible.

    Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy

    • Advise postmenopausal women of the risks for serious adverse reactions of estrogen plus progestin therapy including cardiovascular disorders, malignant neoplasms, and probable dementia.

    Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy

    • Advise postmenopausal women of the risk for less serious but common adverse reactions of estrogen plus progestin therapy (eg, headache, breast pain and tenderness, nausea and vomiting).

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