Estrogens and progestins should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies). Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

DESCRIPTION

PREMPROa 0.3 mg/1.5 mg therapy consists of a single tablet containing 0.3 mg of the conjugated estrogens (CE) found in PremarinO tablets and 1.5 mg of medroxyprogesterone acetate (MPA) for oral administration. PREMPRO 0.45 mg/1.5 mg therapy consists of a single tablet containing 0.45 mg of the conjugated estrogens found in Premarin tablets and 1.5 mg of medroxyprogesterone acetate for oral administration. PREMPRO 0.625 mg/2.5 mg therapy consists of a single tablet containing 0.625 mg of the conjugated estrogens found in Premarin tablets and 2.5 mg of medroxyprogesterone acetate for oral administration. PREMPRO 0.625 mg/5.0 mg therapy consists of a single tablet containing 0.625 mg of the conjugated estrogens found in Premarin tablets and 5 mg of medroxyprogesterone acetate for oral administration. PREMPHASEO therapy consists of two separate tablets, a maroon Premarin tablet containing 0.625 mg of conjugated estrogens that is taken orally on days 1 through 14 and a light-blue tablet containing 0.625 mg of the conjugated estrogens found in Premarin tablets and 5 mg of medroxyprogesterone acetate that is taken orally on days 15 through 28. The conjugated equine estrogens found in Premarin tablets are a mixture of sodium estrone sulfate and sodium equilin sulfate. They contain as concomitant components, as sodium sulfate conjugates, 17 a-dihydroequilin, 17 a-estradiol and 17 b-dihydroequilin. Medroxyprogesterone acetate is a derivative of progesterone. It is a white to off-white, odorless, crystalline powder, stable in air, melting between 200degC and 210degC. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water. The chemical name for MPA is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6a)-. Its molecular formula is C24H34O4, with a molecular weight of 386.53. Its structural formula is:

Each cream tablet for oral administration contains 0.3 mg conjugated estrogens, 1.5 mg medroxyprogesterone acetate, and the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, sucrose, povidone, titanium dioxide, yellow ferric oxide.

Each gold tablet for oral administration contains 0.45 mg conjugated estrogens, 1.5 mg medroxyprogesterone acetate and the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, sucrose, povidone, titanium dioxide, yellow ferric oxide.

Each peach tablet for oral administration contains 0.625 mg conjugated estrogens, 2.5 mg of medroxyprogesterone acetate and the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, sucrose, povidone, titanium dioxide, red ferric oxide.

Each light-blue tablet for oral administration contains 0.625 mg conjugated estrogens, 5 mg of medroxyprogesterone acetate and the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, sucrose, povidone, titanium dioxide, FD&C Blue No. 2.

Each maroon Premarin tablet for oral administration contains 0.625 mg of conjugated estrogens and the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid, sucrose, titanium dioxide, FD&C Blue No. 2, D&C Red No. 27, FD&C Red No. 40. These tablets comply with USP Drug Release Test 1. Each light-blue tablet for oral administration contains 0.625 mg of conjugated estrogens and 5 mg of medroxyprogesterone acetate and the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, sucrose, povidone, titanium dioxide, FD&C Blue No. 2.

CLINICAL PHARMACOLOGY

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, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated 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 follicle stimulating hormone (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.

Pharmacokinetics

Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. However, PREMPRO and PREMPHASE contain a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. MPA is well absorbed from the gastrointestinal tract. Table 1 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens, and medroxyprogesterone acetate following administration of 2 PREMPRO 0.625 mg/2.5 mg and 2 PREMPRO 0.625 mg/5 mg tablets to healthy postmenopausal women.
Table 1. PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA)
DRUG 2 x 0.625 mg CE/2.5 mg MPA Combination Tablets (n=54)	2 x 0.625 mg CE/5 mg MPA Combination Tablets (n=51)
PK Parameter Arithmetic Mean (%CV)	C max (pg/mL)	t max (h)	t 1/2 (h)	AUC (pg * h/mL)	C max (pg/mL)	t max (h)	t 1/2 (h)	AUC (pg * h/mL)
Unconjugated Estrogens Estrone 175 7.6 31.6 5358 (23) (24) (23) (34) BA * -Estrone 159 7.6 16.9 3313 (26) (24) (34) (40) Equilin 71 5.8 9.9 951 (31) (34) (35) (43)	124 10 62.2 6303 (43) (35) (137) (40) 104 10 26.0 3136 (49) (35) (100) (51) 54 8.9 15.5 1179 (43) (34) (53) (56)
PK Parameter Arithmetic Mean (%CV)	C max (ng/mL)	t max (h)	t 1/2 (h)	AUC (ng * h/mL)	C max (ng/mL)	t max (h)	t 1/2 (h)	AUC (ng * h/mL)
Conjugated Estrogens Total Estrone 6.6 6.1 20.7 116 (38) (28) (34) (59) BA * -Total 6.4 6.1 15.4 100 Estrone (39) (28) (34) (57) Total Equilin 5.1 4.6 11.4 50 (45) (35) (25) (70)	6.3 9.1 23.6 151 (48) (29) (36) (42) 6.2 9.1 20.6 139 (48) (29) (35) (40) 4.2 7.0 17.2 72 (52) (36) (131) (50)
PK Parameter Arithmetic Mean (%CV)	C max (ng/mL)	t max (h)	t 1/2 (h)	AUC (ng * h/mL)	C max (ng/mL)	t max (h)	t 1/2 (h)	AUC (ng * h/mL)
Medroxyprogesterone Acetate MPA 1.5 2.8 37.6 37 4.8 2.4 46.3 102 (40) (54) (30) (30) (31) (50) (39) (28)

t1/2 = apparent terminal-phase disposition half-life (0.693/8z) AUC = total area under the concentration-time curve Table 2 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of 2 PREMPRO 0.45 mg/1.5 mg and 2 PREMPRO 0.3 mg/1.5 mg tablets to healthy, postmenopausal women.

t1/2 = apparent terminal-phase disposition half-life (0.693/8z) AUC = total area under the concentration-time curve Food-Effect: Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when PREMPRO or PREMPHASE is administered with a high fat breakfast. Administration with food decreased the Cmax of total estrone by 18 to 34% and increased total equilin Cmax by 38% compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA Cmax and increases MPA AUC by approximately 20 to 30%. Dose Proportionality: The Cmax and AUC values for MPA observed in two separate pharmacokinetic studies conducted with 2 PREMPRO 0.625 mg/2.5 mg or 2 PREMPRO or PREMPHASE 0.625 mg/5 mg tablets exhibited nonlinear dose proportionality; doubling the MPA dose from 2 x 2.5 to 2 x 5.0 mg increased the mean Cmax and AUC by 3.2 and 2.8 folds, respectively. The dose proportionality of estrogens and medroxyprogesterone acetate was assessed by combining pharmacokinetic data across another two studies totaling 61 healthy, postmenopausal women. Single conjugated estrogens doses of 2 x 0.3 mg, 2 x 0.45 mg, or 2 x 0.625 mg were administered either alone or in combination with medroxyprogesterone acetate doses of 2 x 1.5 mg or 2 x 2.5 mg. Most of the estrogen components demonstrated dose proportionality; however, several estrogen components did not. Medroxyprogesterone acetate pharmacokinetic parameters increased in a dose- proportional manner.

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. MPA is approximately 90% bound to plasma proteins but does not bind to SHBG.

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occurs primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

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.

Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Drug Interactions

Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Clinical Studies

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805 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 7 moderate to severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before randomization. PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg were 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. Table 3 shows the adjusted mean number of hot flushes in the PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, 0.3 mg /1.5 mg, and placebo groups during the initial 12-week period.

Table 3: SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY - MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS AND THE PLACEBO GROUP -

PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LOCF

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).

In a 1-year clinical trial of 1376 women (average age 54.0 +- 4.6 years) randomized to 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), results of evaluable biopsies at 12 months (n=279, 274, 277, and 283, respectively) 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). See Table 4.

Table 4. INCIDENCE OF ENDOMETRIAL HYPERPLASIA AFTER ONE YEAR OF TREATMENT
	PREMPRO 0.625 mg/2.5 mg	PREMPRO 0.625 mg/5 mg	PREMPHASE 0.625 mg/5 mg	Premarin 0.625 mg
Total number of patients	340	338	351	347
Number of patients with	279	274	277	283
evaluable biopsies
No. (%) of patients with biopsies
	2 (<1) *	0 (0) *	3 (1) *	57 (20)

*Significant (p < 0.001) in comparison with Premarin (0.625 mg) alone. In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 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 of evaluable endometrial biopsies at 12 months showed a reduced risk of endometrial hyperplasia or cancer in the PREMPRO treatment groups compared with the corresponding Premarin alone treatment groups, except for the PREMPRO 0.3 mg /1.5 mg and Premarin 0.3 mg alone groups, in each of which there was only 1 case. See Table 5. No endometrial hyperplasia or cancer was noted in those patients treated with the continuous combined regimens who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study. See Table 6.

Table 5. INCIDENCE OF ENDOMETRIAL HYPERPLASIA/ CANCERa AFTER ONE YEAR OF TREATMENTb

------------------------------------------------------------- Groups ------------------------------------------------------------

a: All cases of hyperplasia/cancer were endometrial hyperplasia except for 1 patient in the Premarin 0.3 mg group diagnosed with endometrial cancer based on endometrial biopsy, and 1 patient in the Premarin/MPA 0.45 mg/1.5 mg group diagnosed with endometrial cancer based on endometrial biopsy.

b: Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of

hyperplasia/cancer between the two, a third pathologist adjudicated (consensus).

For an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least 2 pathologists had to agree on the diagnosis. d: Significant (p < 0.05) in comparison with corresponding dose of Premarin alone.

TABLE 6. OSTEOPOROSIS AND METABOLIC SUBSTUDY, INCIDENCE OF ENDOMETRIAL HYPERPLASIA/ CANCERa AFTER TWO YEARS OF TREATMENTb

------------------------------------------------------------- Groups ------------------------------------------------------------

a: All cases of hyperplasia/cancer were endometrial hyperplasia in patients who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study.

b: Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, a third pathologist adjudicated (consensus).

The effects of PREMPRO on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in 2 clinical trials. Results are shown in Figures 1 and 2.

FIGURE 1. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING

Note: The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

FIGURE 2. PATIENTS WITH CUMULATIVE AMENORRHEA OVER TIME PERCENTAGES OF WOMEN WITH NO BLEEDING OR SPOTTING

Note: The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of 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 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.

All active treatment groups showed significant differences from placebo in each of the 4 BMD endpoints. These significant differences were seen at cycles 6, 13, 19, and 26. With PREMPRO, the mean percent 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 3.28% with 0.625 mg/2.5 mg, 2.18% with 0.45 mg/1.5 mg, and 1.71% with 0.3 mg/1.5 mg. The placebo group showed a mean percent decrease from baseline at the final evaluation of 2.45%. These results show that the lower dose regimens of PREMPRO were effective in increasing L2 to L4 BMD compared with placebo and, therefore, support the efficacy of lower doses of PREMPRO. The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral trochanter that were generally larger than those seen for L2 to L4 and changes in femoral neck and total body that were generally smaller than those seen for L2 to L4. Significant differences between groups indicated that each of the PREMPRO treatment groups was more effective than placebo for all 3 of these additional BMD endpoints. With regard to femoral neck and total body, the continuous combined treatment groups all showed mean percent increases in BMD while the placebo group showed mean percent decreases. For femoral trochanter, each of the PREMPRO groups showed a mean percent increase that was significantly greater than the small increase seen in the placebo group. The percent changes from baseline to final evaluation are shown in Table 7.

Figure 3 shows the cumulative percentage of subjects with percent changes from baseline in spine BMD equal to or greater than the percent change shown on the x-axis.

Table 7. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION,
Region Evaluated Treatment Group a	No. of Subjects	Baseline (g/cm 2 ) Mean +- SD	Change from Baseline (%) Adjusted Mean +- SE	p-Value vs Placebo
L 2 to L 4 BMD 0.625/2.5	81	1.14 +- 0.16	3.28 +- 0.37	<0.001
0.45/1.5	89	1.16 +- 0.14	2.18 +- 0.35	<0.001
0.3/1.5	90	1.14 +- 0.15	1.71 +- 0.35	<0.001
Placebo	85	1.14 +- 0.14	-2.45 +- 0.36
Total body BMD
0.625/2.5	81	1.14 +- 0.08	0.87 +- 0.17	<0.001
0.45/1.5	89	1.14 +- 0.07	0.59 +- 0.17	<0.001
0.3/1.5	91	1.13 +- 0.08	0.60 +- 0.16	<0.001
Placebo	85	1.13 +- 0.08	-1.50 +- 0.17
Femoral neck BMD
0.625/2.5	81	0.89 +- 0.14	1.62 +- 0.46	<0.001
0.45/1.5	89	0.89 +- 0.12	1.48 +- 0.44	<0.001
0.3/1.5	91	0.86 +- 0.11	1.31 +- 0.43	<0.001
Placebo	85	0.88 +- 0.14	-1.72 +- 0.45
Femoral trochanter BMD
0.625/2.5	81	0.77 +- 0.14	3.35 +- 0.59	0.002
0.45/1.5	89	0.76 +- 0.12	2.84 +- 0.57	0.011
0.3/1.5	91	0.76 +- 0.12	3.93 +- 0.56	<0.001
Placebo	85	0.75 +- 0.12	0.81 +- 0.58

Figure 3. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN/MPA 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 4. Significant differences between each of the PREMPRO dosage groups and placebo were found at cycles 6, 13, 19, and 26.

Figure 4. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN/MPA 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; 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.

A substudy of the Women's Health Initiative (WHI) enrolled 16,608 predominantly healthy postmenopausal women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic) to assess the risks and benefits of 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 PREMPRO on menopausal symptoms. 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 are presented in Table 8 below:

events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes

* 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 WARNING, WARNINGS and PRECAUTIONS.)

CONTRAINDICATIONS

Estrogens/progestins combined should not be used in women with any of the following conditions:

WARNINGS

Cardiovascular disorders.

Estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogen/progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus should be managed appropriately.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving PREMPRO compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the PREMPRO-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the PREMPRO group and the placebo group in HERS, HERS II, and overall.

Large d oses of estrogen (5 m g conju gated estrogens p er d ay), comp arable to those u sed to treat cancer of the p rostate and breast, have been show n in a large p rosp ective clinical trial in m en to increase the risk of

nonfatal m yocard ial infarction, pu lm onary em bolism , and throm bop hlebitis.

Venous thromboembolism (VTE). In the PREMPRO substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the PREMPRO group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.) If feasible, estrogens should be discontinued 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.

with an increased risk of breast cancer. In the PREMPRO substudy of the Women's Health Initiative study, a 26% increase of invasive breast cancer (38 vs 30 per 10,000 woman-years) after an average of 5.2 years of treatment was observed in women receiving PREMPRO compared to women receiving placebo. The increased risk of breast cancer became apparent after 4 years on PREMPRO. The women reporting prior postmenopausal use of estrogen and/or estrogen with progestin had a higher relative risk for breast cancer associated with PREMPRO than those who had never used these hormones. (See CLINICAL PHARMACOLOGY, Clinical Studies.) Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens, with or without progestin. This association was reanalyzed in original data from 51 studies that involved treatment with various doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continued treatment, and subsided after treatment had been discontinued for about 5 years. Some later studies have suggested that treatment with estrogen and progestin increases the risk of breast cancer more than treatment with estrogen alone. A postmenopausal woman without a uterus who requires estrogen should receive estrogen-alone therapy and should not be exposed unnecessarily to progestins. All postmenopausal women should receive yearly breast exams by a healthcare provider and perform monthly breast self- examinations. In addition, mammography examinations should be scheduled based on patient age and risk factors.

The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal 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. Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1% or less with PREMPRO or PREMPHASE in two large clinical trials. In the two large clinical trials described above, two cases of endometrial cancer were reported to occur among women taking combination Premarin/medroxyprogesterone acetate therapy.

Gallbladder Disease.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Hypercalcemia.

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Visual Abnormalities.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued.

PRECAUTIONS

General

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared with estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of glucose tolerance.

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg compared with placebo were 32.8, 24.8, 23.3, and 10.7, respectively. After two years of treatment, the mean percent changes were 33.0, 17.1, 21.6, and 5.5, respectively.

Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Because estrogens/progestins may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

Use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a significant association. Data are insufficient to determine whether there is an increased risk with combined estrogen/progestin therapy in postmenopausal women.

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Patient Information

Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMPRO or PREMPHASE.

Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

Drug/Laboratory Test Interactions

alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels. Impaired glucose tolerance. Reduced response to metyrapone test. Aminoglutethimide administered concomitantly with medroxyprogesterone acetate (MPA) may significantly depress the bioavailability of MPA.

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 breasts, uterus, cervix, vagina, testis, and liver. (See BOXED WARNING, CONTRAINDICATIONS and WARNINGS.) In a two-year oral study of medroxyprogesterone acetate (MPA) in which female rats were exposed to dosages of up to 5000 mcg/kg/day in their diets (50 times higher - based on AUC values - than the level observed experimentally in women taking 10 mg of MPA), a dose-related increase in pancreatic islet cell tumors (adenomas and carcinomas) occurred. Pancreatic tumor incidence was increased at 1000 and 5000 mcg/kg/day, but not at 200 mcg/kg/day. A decreased incidence of spontaneous mammary gland tumors was observed in all three MPA-treated groups, compared with controls, in the two-year rat study. The mechanism for the decreased incidence of mammary gland tumors observed in the MPA-treated rats may be linked to the significant decrease in serum prolactin concentration observed in rats. Beagle dogs treated with MPA developed mammary nodules, some of which were malignant. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas the nodules in the drug-treated animals were larger, more numerous, persistent, and there were some breast malignancies with metastases. It is known that progestogens stimulate synthesis and release of growth hormone in dogs. The growth hormone, along with the progestogen, stimulates mammary growth and tumors. In contrast, growth hormone in humans is not increased, nor does growth hormone have any significant mammotrophic role. No pancreatic tumors occurred in dogs.

Pregnancy

PREMPRO and PREMPHASE should not be used during pregnancy. (See CONTRAINDICATIONS.)

Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogen and progestin have been identified in the milk of mothers receiving these drugs. Caution should be exercised when PREMPRO or PREMPHASE are administered to a nursing woman.

Pediatric Use

Geriatric Use

Of the total number of subjects in the PREMPRO substudy of the Women's Health Initiative study, 44% (n = 7320) 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 and medroxyprogesterone acetate to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE.

ADVERSE REACTIONS

See BOXED WARNING, WARNINGS and PRECAUTIONS. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. In a 1-year clinical trial that included 678 postmenopausal women treated with PREMPRO, 351 postmenopausal women treated with PREMPHASE, and 347 postmenopausal women treated with Premarin, the following adverse events occurred at a rate 3 5% (see Table 9):

Table 9. ALL TREATMENT EMERGENT STUDY EVENTS REGARDLESS OF DRUG RELATIONSHIP REPORTED AT A FREQUENCY 3 5%
	PREMPRO 0.625 mg/2.5 mg continuous (n=340)	PREMPRO 0.625 mg/5.0 mg continuous (n=338)	PREMPHASE 0.625 mg/5.0 mg sequential (n=351)	PREMARIN 0.625 mg daily (n=347)
Body as a whole abdominal pain	16%	21%	23%	17%
accidental injury	5%	4%	5%	5%
asthenia	6%	8%	10%	8%
back pain	14%	13%	16%	14%
flu syndrome	10%	13%	12%	14%
headache	36%	28%	37%	38%
infection	16%	16%	18%	14%
pain	11%	13%	12%	13%
pelvic pain Digestive system diarrhea	4% 6%	5% 6%	5% 5%	5% 10%
dyspepsia	6%	6%	5%	5%
flatulence	8%	9%	8%	5%
nausea	11%	9%	11%	11%
Metabolic and Nutritional
peripheral edema Musculoskeletal system arthralgia	4% 9%	4% 7%	3% 9%	5% 7%
leg cramps Nervous system depression	3% 6%	4% 11%	5% 11%	4% 10%
dizziness	5%	3%	4%	6%
hypertonia Respiratory system	4%	3%	3%	7%
pharyngitis	11%	11%	13%	12%
rhinitis	8%	6%	8%	7%
sinusitis Skin and appendages pruritus	8% 10%	7% 8%	7% 5%	5% 4%
rash	4%	6%	4%	3%
Urogenital system breast pain	33%	38%	32%	12%
cervix disorder	4%	4%	5%	5%
dysmenorrhea	8%	5%	13%	5%
leukorrhea	6%	5%	9%	8%
vaginal hemorrhage	2%	1%	3%	6%

vaginitis 7% 7% 5% 3%

During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65 years of age (88% Caucasian), 2001women received continuous regimens of either 0.625 mg of CE with or without 2.5 mg MPA, or 0.45 mg or 0.3 mg of CE with or without 1.5 mg MPA, and 332 received placebo tablets. Table 10 summarizes adverse events that occurred at a rate 5% in at least 1 treatment group.

Body System Adverse event	Premarin 0.625 mg daily (n = 348)	Prempro 0.625 mg/2.5 mg continuous (n = 331)	Premarin 0.45 mg daily (n = 338)	Prempro 0.45 mg/1.5 mg continuous (n = 331)	Premarin 0.3 mg daily (n = 326)	Prempro 0.3 mg/1.5 mg continuous (n = 327)	Placebo daily (n = 332)
Any adverse event	93%	92%	90%	89%	90%	90%	85%
Body as a whole abdominal pain	16%	17%	15%	16%	17%	13%	11%
accidental injury	6%	10%	12%	9%	6%	9%	9%
asthenia	7%	8%	7%	8%	8%	6%	5%
back pain	14%	12%	13%	13%	13%	12%	12%
flu syndrome	11%	8%	11%	11%	10%	10%	11%
headache	26%	28%	32%	29%	29%	33%	28%
infection	18%	21%	22%	19%	23%	18%	22%
pain	17%	14%	18%	15%	20%	20%	18%
Digestive system
diarrhea	6%	7%	7%	7%	6%	6%	6%
dyspepsia	9%	8%	9%	8%	11%	8%	14%
flatulence	7%	7%	7%	8%	6%	5%	3%
nausea	9%	7%	7%	10%	6%	8%	9%
Musculoskeletal system
arthralgia	14%	9%	12%	13%	7%	10%	12%
leg cramps	5%	7%	7%	5%	3%	4%	2%
myalgia	5%	5%	5%	5%	9%	4%	8%
Nervous system anxiety	5%	4%	4%	5%	4%	2%	4%
depression	7%	11%	8%	5%	5%	8%	7%
dizziness	6%	3%	6%	5%	4%	5%	5%
insomnia	6%	6%	7%	7%	7%	6%	10%

nervousness 3% 3% 5% 2% 2% 2% 2%

Body System Adverse event	Premarin 0.625 mg daily (n = 348)	Prempro 0.625 mg/2.5 mg continuous (n = 331)	Premarin 0.45 mg daily (n = 338)	Prempro 0.45 mg/1.5 mg continuous (n = 331)	Premarin 0.3 mg daily (n = 326)	Prempro 0.3 mg/1.5 mg continuous (n = 327)	Placebo daily (n = 332)
Respiratory system
cough increased	4%	8%	7%	5%	4%	6%	4%
pharyngitis	10%	11%	10%	8%	12%	9%	11%
rhinitis	6%	8%	9%	9%	10%	10%	13%
sinusitis	6%	8%	11%	8%	7%	10%	7%
upper respiratory infection	12%	10%	10%	9%	9%	11%	11%
Skin and appendages
pruritus	4%	4%	5%	5%	5%	5%	2%
breast enlargement	<1%	5%	1%	3%	2%	2%	<1%
breast pain	11%	26%	12%	21%	7%	13%	9%
dysmenorrhea	4%	5%	3%	6%	1%	3%	<1%
leukorrhea	5%	4%	7%	5%	4%	3%	3%
vaginal hemorrhage	14%	6%	4%	4%	2%	2%	0%
vaginal moniliasis	6%	8%	5%	7%	5%	4%	2%

Urogenital system

vaginitis 7% 5% 6% 6% 5% 4% 1%

The following additional adverse reactions have been reported with estrogen and/or progestin therapy:

Genitourinary system

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, change in amount of cervical secretion, premenstrual-like syndrome, cystitis- like syndrome, increase in size of uterine leiomyomata, vaginal candidiasis, amenorrhea, changes in cervical erosion, ovarian cancer, endometrial hyperplasia, endometrial cancer.

Breasts

Tenderness, enlargement, pain, nipple discharge, galactorrhea, fibrocystic breast changes, breast cancer.

Cardiovascular

Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.

Gastrointestinal

Nausea, cholestatic jaundice, changes in appetite, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas.

Skin

Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, itching, urticaria, pruritus, generalized rash, rash (allergic) with and without pruritus, acne.

Eyes

Neuro-ocular lesions, e.g., retinal vascular thrombosis and optic neuritis, steepening of corneal curvature, intolerance of contact lenses.

Central Nervous System (CNS)

Headache, dizziness, mental depression, mood disturbances, anxiety, irritability, nervousness, migraine, chorea, insomnia, somnolence, exacerbation of epilepsy.

Miscellaneous

Increase or decrease in weight, edema, changes in libido, fatigue, backache, reduced carbohydrate tolerance, aggravation of porphyria, pyrexia, urticaria, angioedema, anaphylactoid/anaphylactic reactions, hypocalcemia, exacerbation of asthma, increased triglycerides.

OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of estrogen/progestin-containing oral contraceptives by young children. Overdosage of estrogen/progestin may cause nausea and vomiting, and withdrawal bleeding may occur in females.

DOSAGE AND ADMINISTRATION

Use of estrogens, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (e.g., at 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNING and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. PREMPRO therapy consists of a single tablet to be taken once daily.

Patients should be treated with the lowest effective dose. Generally women should be started at 0.3 mg/1.5 mg PREMPRO daily. Subsequent dosage adjustment may be made based upon the individual patient response. In patients where bleeding or spotting remains a problem, after appropriate evaluation, consideration should be given to changing the dose level. This dose should be periodically reassessed by the healthcare provider. For prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.

Patients should be treated with the lowest effective dose. Generally women should be started at 0.3 mg/ 1.5 mg PREMPRO daily. Dosage may be adjusted depending on individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider. In patients where bleeding or spotting remains a problem, after appropriate evaluation, consideration should be given to changing the dose level. This dose should be periodically reassessed by the healthcare provider. PREMPHASE therapy consists of two separate tablets; one maroon 0.625 mg Premarin tablet taken daily on days 1 through 14 and one light-blue tablet, containing 0.625 mg conjugated estrogens and 5 mg of medroxyprogesterone acetate, taken on days 15 through 28.

HOW SUPPLIED

Each carton contains 3 EZ DIALa dispensers containing 28 tablets. One EZ DIAL dispenser contains 28 oval, cream tablets containing 0.3 mg of the conjugated estrogens found in Premarin tablets and 1.5 mg medroxyprogesterone acetate for oral administration (NDC 0046-0938-09).

Each carton includes 3 EZ DIAL dispensers containing 28 tablets. One EZ DIAL dispenser contains 28 oval, gold tablets containing 0.45 mg of the conjugated estrogens found in Premarin tablets and 1.5 mg medroxyprogesterone acetate for oral administration (NDC 0046-0937-09).

Each carton includes 3 EZ DIAL dispensers containing 28 tablets. One EZ DIAL dispenser contains 28 oval, peach tablets containing 0.625 mg of the conjugated estrogens found in Premarin tablets and 2.5 mg of medroxyprogesterone acetate for oral administration (NDC 0046-0875-06).

Each carton includes 3 EZ DIAL dispensers containing 28 tablets. One EZ DIAL dispenser contains 28 oval, light-blue tablets containing 0.625 mg of the conjugated estrogens found in Premarin tablets and 5 mg of medroxyprogesterone acetate for oral administration (NDC 0046-0975-06). PREMPHASE therapy consists of two separate tablets; one maroon Premarin tablet taken daily on days 1 through 14 and one light-blue tablet taken on days 15 through 28. Each carton includes 3 EZ DIAL dispensers containing 28 tablets. One EZ DIAL dispenser contains 14 oval, maroon Premarin tablets containing 0.625 mg of conjugated estrogens and 14 oval, light-blue tablets that contain 0.625 mg of the conjugated estrogens found in Premarin tablets and 5 mg of medroxyprogesterone acetate for oral administration (NDC 0046-2573-06). The appearance of PREMPRO tablets is a trademark of Wyeth Pharmaceuticals. The appearance of Premarin tablets is a trademark of Wyeth Pharmaceuticals. The appearance of the conjugated estrogens/medroxyprogesterone acetate combination tablets is a registered trademark.

Table 8. RELATIVE AND ABSOLUTE RISK SEEN IN THE PREMPRO SUBSTUDY OF WHI a
Event c	Relative Risk PREMPRO vs Placebo at 5.2 Years (95% CI *)	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

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PREMPRO(tm)

PREMPHASEa

only

WARNING