Premarin

[Conjugated Estrogens]

TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT
POPULATION, LAST OBSERVATION CARRIED FORWARD
Region Evaluated
Treatment Group a
No. of
Subjects
Baseline (g/ cm 2 )
Mean ± SD
Change from Baseline (%)
Adjusted Mean ± SE
p-Value vs
Placebo
Total Body BMD
0.625 84 1.15 ± 0.08 0.68 ± 0.17 < 0.001
0.45 91 1.14 ± 0.08 0.74 ± 0.16 < 0.001
0.3 87 1.14 ± 0.07 0.40 ± 0.17 < 0.001
Placebo 85 1.13 ± 0.08 -1.50 ± 0.17

Femoral Neck BMD
0.625 84 0.91 ± 0.14 1.82 ± 0.45 < 0.001
0.45 91 0.89 ± 0.13 1.84 ± 0.44 < 0.001
0.3 87 0.86 ± 0.11 0.62 ± 0.45 < 0.001
Placebo 85 0.88 ± 0.14 -1.72 ± 0.45

Femoral Trochanter BMD
0.625 84 0.78 ± 0.13 3.82 ± 0.58 < 0.001
0.45 91 0.76 ± 0.12 3.16 ± 0.56 0.003
0.3 87 0.75 ± 0.10 3.05 ± 0.57 0.005
Placebo 85 0.75 ± 0.12 0.81 ± 0.58
a: Identified by dosage (mg) of Premarin or placebo.

Text Continues Below

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Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater than the value shown on the x-axis.

Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN AND PLACEBO GROUPS

The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 2. Significant differences between each of the Premarin dosage groups and placebo were found at cycles 6, 13, 19, and 26.

Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH
CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS AND PLACEBO

The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (p 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with 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.

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of Premarin (0.625 mg conjugated equine estrogens per day) alone or the use of Prempro (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of Premarin or Prempro on menopausal symptoms.

The Premarin-only substudy is continuing and results have not been reported. The Prempro substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the Prempro substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 4 below.

TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE PREMPRO SUBSTUDY OF WHI a
Placebo
n = 8102
Prempro
n = 8506

Event c Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*) Absolute Risk per 10,000 Person-years
CHD events 1.29 (1.02-1.63) 30 37
Non-fatal MI 1.32 (1.02-1.72) 23 30
CHD death 1.18 (0.70-1.97) 6 7
Invasive breast cancer b 1.26 (1.00-1.59) 30 38
Stroke 1.41 (1.07-1.85) 21 29
Pulmonary embolism 2.13 (1.39-3.25) 8 16
Colorectal cancer 0.63 (0.43-0.92) 16 10
Endometrial cancer 0.83 (0.47-1.47) 6 5
Hip fracture 0.66 (0.45-0.98) 15 10
Death due to causes other than
the events above
0.92 (0.74-1.14) 40 37

Global Index c 1.15 (1.03-1.28) 151 170
Deep vein thrombosis d 2.07 (1.49-2.87) 13 26
Vertebral fractures d 0.66 (0.44-0.98) 15 9
Other osteoporotic fractures d 0.77 (0.69-0.86) 170 131
a: adapted from JAMA, 2002; 288: 321-333
b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c: a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
d: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

For those outcomes included in the "global index," absolute excess risks per 10,000 person-years in the group treated with Prempro were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and
PRECAUTIONS.)

Drug/ Laboratory Test Interactions

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.

3. Other binding proteins may be elevated in serum, i. e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/ renin substrate, alpha-1-
antitrypsin, ceruloplasmin).

4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.

5. Impaired glucose tolerance.

6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See BOXED WARNINGS, CONTRAINDICATIONS, andWARNINGS).

F. Pregnancy

Premarin should not be used during pregnancy. (See CONTRAINDICATIONS).

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Premarin is administered to a nursing woman.

H. Pediatric Use

Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.

Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND ADMINISTRATION sections.

I. Geriatric Use

Of the total number of subjects in the Prempro substudy of the Women's Health Initiative study, 44% (n= 7,320) were 65 years and over, while 6.6% (n= 1,095) were 75 and over (see CLINICAL PHARMACOLOGY, Clinical Studies). No significant differences in safety were observed between subjects 65 years and over compared to younger subjects. There was a higher incidence of stroke and invasive breast cancer in women 75 and over compared to younger subjects.

With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ from younger subjects in their response to Premarin.

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