Prempro 0.3mg/1.5mg

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).