General Information

Premarin for oral administration contains a mixture of conjugated estrogens obtained exclusively from natural sources.

Premarin is specifically indicated for the following:

• Treatment of moderate to severe vasomotor symptoms due to menopause
• Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause
• Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure
   
• Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease
   
• Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only)
   
• Prevention of postmenopausal osteoporosis

Mechanism of Action

Premarin for oral administration contains a mixture of conjugated estrogens 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.

Side Effects

Adverse events associated with the use of Premarin may include, but are not limited to, the following:

• Headache infection
• Pain
• Abdominal pain
• Back pain
• Arthralgia
• Vaginal hemorrhage
• Upper respiratory infection

Dosing/Administration

Premarin is supplied as tablets for oral administration. It was subsequently approved in cream and intravenous formulations. The recommended initial dose of Premarin tablets is as follows:

1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of vulvar and vaginal atrophy due to menopause: The lowest effective dose should be administered. Generally, Premarin should be started at 0.3 mg daily. Subsequent dosage adjustment may be made based upon the individual response.
2. For prevention of postmenopausal osteoporosis: The lowest effective dose should be administered. Generally, Premarin should be started at 0.3 mg daily. Subsequent dosage adjustment may be made based upon the individual clinical and bone mineral density responses.
3. For treatment of female hypoestrogenism due to hypogonadism, castration or primary ovarian failure:
Female hypogonadism: 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off).
Female castration or primary ovarian failure: 1.25 mg daily, cyclically. Adjust dosage, upward or downward, according to severity of symptoms and patient response.
4. For treatment of breast cancer, for palliation only: 10 mg three times daily for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only: 1.25 mg to 2 x 1.25 mg three times daily.

Clinical Trial Results

FDA Approval
The FDA approval of Premarin was based on the following studies:

Vasomotor symptoms
Data are from 2,805 postmenopausal women enrolled in the HOPE Study. The women were randomly assigned to one of eight treatment groups, receiving 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. Premarin (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms.
 

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 < 0.001) for all treatment groups (conjugated estrogens alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).
 

Effects on bone mineral density
Data is from the double-blind, randomized, placebo/active-drug-controlled, multicenter HOPE study. The study enrolled healthy postmenopausal women with an intact uterus, who were 2.3 ± 0.9 years on average since menopause and took one 600-mg tablet of elemental calcium (Caltrate) daily. The subjects were treated with Premarin 0.625 mg, 0.45 mg, 0.3 mg 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. All active treatment groups showed significant differences from placebo in each of the four BMD end points at cycles 6, 13, 19 and 26. The mean percentage increases in the primary efficacy measure (L2 to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available evaluation for those who discontinued early) were 2.46 percent with 0.625 mg, 2.26 percent with 0.45 mg and 1.13 percent with 0.3 mg. The placebo group showed a mean percentage decrease from baseline at the final evaluation of 2.45 percent. These results supported the efficacy of the lower doses.