Menopause and HRT:
Indications for: PREMPRO 0.3mg/1.5mg
Moderate-to-severe vasomotor symptoms of menopause. Moderate-to-severe vulvar and vaginal atrophy due to menopause. Prevention of postmenopausal osteoporosis.
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.
1 tab once daily.
PREMPRO 0.3mg/1.5mg Contraindications:
Undiagnosed abnormal genital bleeding. Breast or other estrogen-dependent neoplasms. Thromboembolic disorders (eg, DVT, PE, stroke, MI). Protein C, protein S, or antithrombin deficiency, or other thrombophilias. Hepatic impairment or disease. Pregnancy.
Endometrial cancer. Breast cancer. Cardiovascular disorders. Probable dementia.
PREMPRO 0.3mg/1.5mg 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. History of hypertriglyceridemia. Discontinue if cholestatic jaundice, pancreatitis, hypercalcemia, or retinal vascular lesions occur. 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.
PREMPRO 0.3mg/1.5mg Classification:
Estrogen + progestin.
PREMPRO 0.3mg/1.5mg 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).
Abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, leukorrhea; thromboembolism, neoplasms, anaphylaxis, angioedema (permanently discontinue if occurs).
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.
Blister card (28 tabs)—1