Prempro/Premphase - 3 indications

Scroll down for information on each indication:

• the treatment of moderate to severe vasomotor symptoms due to menopause; approved 1995
• the treatment of moderate to severe vulvar and vaginal atrophy due to menopause; approved 1995
• the prevention of postmenopausal osteoporosis; approved 1995

General Information

Prempro/Premphase is an estrogen plus progestin hormone replacement therapy.

Prempro/Premphase is specifically indicated for:

• the treatment of moderate to severe vasomotor symptoms due to menopause
• the treatment of moderate to severe vulvar and vaginal atrophy due to menopause 
• the prevention of postmenopausal osteoporosis 

Prempro/Premphase are supplied as tablets for oral administration. The recommended dose is as follows:

Prempro: one tablet containing conjugated estrogens (CE) plus medroxyprogesterone acetate (MPA) taken orally once daily. 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.

Mechanism 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 sulfateconjugated 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.

Side Effects

Adverse effects associated with the use of Prempro/Premphase may include, but are not limited to, the following:

• abdominal pain
• asthenia
• back pain
• headache
• flatulence
• nausea
• depression
• pruritus
• breast pain
• dysmenorrhea
• leukorrhea

The drug label comes with the following Black Box Warning: 

Estrogen Plus Progestin Therapy: Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. The Women’s Health Initiative (WHI) estrogen plus progestin sub-study reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI), as well as increased risks of invasive breast cancer. 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.

Estrogen-Alone Therapy: There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia. The WHI estrogen-alone substudy reported increased risks of stroke and DVT . The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older.

Indication 1 - moderate to severe vasomotor symptoms due to menopause

approved 1995

Clinical Trial Results

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 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 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..

Indication 2 - moderate to severe vulvar and vaginal atrophy due to menopause

approved 1995

Clinical Trial Results

Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant for all treatment groups.

Indication 3 - prevention of postmenopausal osteoporosis

approved 1995

Clinical Trial Results

Effects on Bone Mineral Density: Data was gathered from the HOPE study. 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 not given Vitamin D supplements. They 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. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26. Intent-to-treat subjects All active treatment groups showed significant differences from placebo in each of the four BMD endpoints. These significant differences were seen at cycles 6, 13, 19, and 26. The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density study showed significant differences between each of the Prempro dosage groups and placebo at cycles 6, 13, 19, and 26.