PREMPRO 0.3/1.5 28 Day Pack

Details

Generic Name: CONJUGATED ESTROGENS AND MEDROXYPROGESTERONE ACETATE

Brand Name: Prempro

Substance Name(s):
ESTROGENS, CONJUGATED
MEDROXYPROGESTERONE ACETATE

DRUG INTERACTIONS

7 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 CE plus MPA.

Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism (7) Aminoglutethimide administered concomitantly with MPA may significantly depress the bioavailability of medroxyprogesterone acetate (7) 7.1 Metabolic Interactions 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 (Hypericum perforatum) preparations, 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.

Aminoglutethimide administered concomitantly with MPA may significantly depress the bioavailability of MPA.

OVERDOSAGE

10 Overdosage of estrogen or estrogen plus progestin may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding may occur in women.

Treatment of overdose consists of discontinuation of PREMPRO or PREMPHASE therapy with institution of appropriate symptomatic care.

DESCRIPTION

11 Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture 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.

It contains as concomitant components, as sodium sulfate conjugates, 17 α-dihydroequilin, 17 α‑estradiol and 17 β-dihydroequilin.

Medroxyprogesterone acetate is a derivative of progesterone.

It is a white to off-white, odorless, crystalline powder, stable in air, melting between 200°C and 210°C.

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-, (6α)-.

Its molecular formula is C24H34O4, with a molecular weight of 386.53.

Its structural formula is: PREMPRO 0.3 mg/1.5 mg, 0.45 mg/1.5 mg, and 0.625 mg/2.5 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, microcrystalline cellulose, hypromellose, hydroxypropyl cellulose, sucrose, Eudragit NE 30D, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide.

PREMPRO 0.625 mg/5 mg tablets contain 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, and black iron oxide.

PREMPHASE Each maroon Premarin tablets for oral administration contain 0.625 mg of conjugated estrogens and the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, titanium dioxide, FD&C Blue No.

2, and FD&C Red No.

40.

These tablets comply with USP Dissolution Test 5.

Each light-blue tablet for oral administration contains 0.625 mg of 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, and black iron oxide.

PREMPRO Tablet Strength Tablet Color Contains 0.3 mg/1.5 mg Yellow iron oxide and black iron oxide 0.45 mg/1.5 mg Yellow iron oxide and black iron oxide 0.625 mg/2.5 mg Red iron oxide, yellow iron oxide, and black iron oxide 0.625 mg/5 mg FD&C Blue No.

2 and black iron oxide PREMPHASE Tablet Strength Tablet Color Contains 0.625 mg FD&C Blue No.

2 and FD&C Red No.

40 0.625 mg/5 mg FD&C Blue No.

2 and black iron oxide Chemical Structure

CLINICAL STUDIES

14 14.1 Effects on Vasomotor Symptoms 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.

Table 5 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 5: 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, LAST OBSERVATION CARRIED FORWARD (LOCF) Treatmenta (No.

of Patients) ——————-No.

of Hot Flushes/Day—————– a Identified by dosage (mg) of Premarin/MPA or placebo.

b There were no statistically significant differences between the 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg groups at any time period.

Time Period (week) Baseline Mean ± SD Observed Mean ± SD Mean Change ± SD p-Values vs.

Placebob 0.625 mg/2.5 mg (n = 34) 4 11.98 ± 3.54 3.19 ± 3.74 -8.78 ± 4.72 <0.001 12 11.98 ± 3.54 1.16 ± 2.22 -10.82 ± 4.61 <0.001 0.45 mg/1.5 mg (n = 29) 4 12.61 ± 4.29 3.64 ± 3.61 -8.98 ± 4.74 <0.001 12 12.61 ± 4.29 1.69 ± 3.36 -10.92 ± 4.63 <0.001 0.3 mg/1.5 mg (n = 33) 4 11.30 ± 3.13 3.70 ± 3.29 -7.60 ± 4.71 <0.001 12 11.30 ± 3.13 1.31 ± 2.82 -10.00 ± 4.60 <0.001 Placebo (n = 28) 4 11.69 ± 3.87 7.89 ± 5.28 -3.80 ± 4.71 – 12 11.69 ± 3.87 5.71 ± 5.22 -5.98 ± 4.60 – 14.2 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.

14.3 Effects on the Endometrium In a 1-year clinical trial of 1,376 women (average age 54 ± 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 percent) and in the PREMPHASE treatment group (less than 1 percent; 1 percent when focal hyperplasia was included) compared to the Premarin group (8 percent; 20 percent when focal hyperplasia was included), see Table 6.

TABLE 6: INCIDENCE OF ENDOMETRIAL HYPERPLASIA AFTER ONE YEAR OF TREATMENT ————————–Groups————————- * Significant (p < 0.001) in comparison with Premarin (0.625 mg) alone.

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 evaluable biopsies 279 274 277 283 No.

(%) of patients with biopsies: • All focal and non-focal hyperplasia 2 (<1)* 0 (0)* 3 (1)* 57 (20) • Excluding focal cystic hyperplasia 2 (<1)* 0 (0)* 1 (<1)* 25 (8) In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 2,001 women (average age 53.3 ± 4.9 years), of whom 88 percent 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 7.

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 8.

TABLE 7: 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).

c 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.

e Non-significant in comparison with corresponding dose of Premarin alone.

Patient Prempro 0.625 mg/ 2.5 mg Premarin 0.625 mg Prempro 0.45 mg/ 1.5 mg Premarin 0.45 mg Prempro 0.3 mg/ 1.5 mg Premarin 0.3 mg Total number of patients 331 348 331 338 327 326 Number of patients with evaluable biopsies 278 249 272 279 271 269 No.

(%) of patients with biopsies: • Hyperplasia/cancera (consensusc) 0 (0)d 20 (8) 1 (<1)a,d 9 (3) 1 (<1)e 1 (<1)a TABLE 8: 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).

c 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.

Patient Prempro 0.625 mg/ 2.5 mg Premarin 0.625 mg Prempro 0.45 mg/ 1.5 mg Premarin 0.45 mg Prempro 0.3 mg/ 1.5 mg Premarin 0.3 mg Total number of patients 75 65 75 74 79 73 Number of patients with evaluable biopsies 62 55 69 67 75 63 No.

(%) of patients with biopsies: • Hyperplasia/cancera (consensusc) 0 (0)d 15 (27) 0 (0)d 10 (15) 0 (0)d 2 (3) 14.4 Effects on Uterine Bleeding or Spotting 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 AT A GIVEN CYCLE THROUGH CYCLE 13 INTENT-TO-TREAT POPULATION, LOCF 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.

If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

Figure 1 Figure 2 14.5 Effects on Bone Mineral Density Health and Osteoporosis, Progestin and Estrogen (HOPE) Study 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.

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 percent changes from baseline to final evaluation are shown in Table 9.

TABLE 9: PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION, LOCF Region Evaluated Treatment Groupa No.

of Subjects Baseline (g/cm2) Mean ± SD Change from Baseline (%) Adjusted Mean ± SE p-Value vs.

Placebo a Identified by dosage (mg/mg) of Premarin/MPA or placebo.

L2 to L4 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 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.

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.

Figure 3 Figure 4 14.6 Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases.

The primary endpoint was the incidence of coronary heart disease [(CHD) defined as nonfatal myocardial infarction (MI), silent MI and CHD death], with invasive breast cancer as the primary adverse outcome.

A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes.

These substudies did not evaluate the effects of CE plus MPA or CE on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early.

According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 10.

These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 10: Relative and Absolute Risk Seen In The Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa,b Relative Risk CE/MPA vs.

Placebo (95% nCIc) CE/MPA n = 8,506 Placebo n = 8,102 a Adapted from numerous WHI publications.

WHI publications can be viewed at www.nhlbi.nih.gov/whi.

b Results are based on centrally adjudicated data.

c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

d Not included in “global index.” e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.

f All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.

g 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, colorectal cancer, hip fracture, or death due to other causes.

Event Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99–1.53) 41 34 Non-fatal MI c 1.28 (1.00–1.63) 31 25 CHD death 1.10 (0.70–1.75) 8 8 All Strokes 1.31 (1.03–1.68) 33 25 Ischemic stroke 1.44 (1.09–1.90) 26 18 Deep vein thrombosisd 1.95 (1.43–2.67) 26 13 Pulmonary embolism 2.13 (1.45–3.11) 18 8 Invasive breast cancere 1.24 (1.01–1.54) 41 33 Colorectal cancer 0.61 (0.42–0.87) 10 16 Endometrial cancerd 0.81 (0.48–1.36) 6 7 Cervical cancerd 1.44 (0.47–4.42) 2 1 Hip fracturec 0.67 (0.47–0.96) 11 16 Vertebral fracturesd 0.65 (0.46–0.92) 11 17 Lower arm/wrist fracturesd 0.71 (0.59–0.85) 44 62 Total fracturesd 0.76 (0.69–0.83) 152 199 Overall Mortalityf 1.00 (0.83-1.19) 52 52 Global Indexg 1.13 (1.02-1.25) 184 165 Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile.

The WHI estrogen plus progestin substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI 0.44-1.07)].

WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 11.

Table 11: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa Relative Risk CE vs.

Placebo (95% nCIb) CE n = 5,310 Placebo n = 5,429 a Adapted from numerous WHI publications.

WHI publications can be viewed at www.nhlbi.nih.gov/whi.

b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.

d Not included in “global index.” e Results are based on an average follow-up of 6.8 years.

f All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.

Event Absolute Risk per 10,000 Women-Years CHD eventsc 0.95 (0.78–1.16) 54 57 Non-fatal MI c 0.91 (0.73–1.14) 40 43 CHD deathc 1.01 (0.71–1.43) 16 16 All Strokec 1.33 (1.05–1.68) 45 33 Ischemicc 1.55 (1.19–2.01) 38 25 Deep vein thrombosisc,d 1.47 (1.06–2.06) 23 15 Pulmonary embolismc 1.37 (0.90–2.07) 14 10 Invasive breast cancerc 0.80 (0.62–1.04) 28 34 Colorectal cancere 1.08 (0.75–1.55) 17 16 Hip fracturec 0.65 (0.45–0.94) 12 19 Vertebral fracturesc,d 0.64 (0.44–0.93) 11 18 Lower arm/wrist fracturesc,d 0.58 (0.47–0.72) 35 59 Total fracturesc,d 0.71 (0.64–0.80) 144 197 Death due to other causese,f 1.08 (0.88–1.32) 53 50 Overall mortalityc,d 1.04 (0.88–1.22) 79 75 Global Indexg 1.02 (0.92–1.13) 206 201 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.9 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 [see Boxed Warnings, and Warnings and Precautions ( 5 )].

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo.

Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined, see Table 10.10 Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile.

The WHI estrogen-alone substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI 0.46-1.11)].

14.7 Women’s Health Initiative Memory Study The estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent 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 (0.625 mg) plus MPA (2.5 mg) versus placebo was 2.05 (95 percent CI 1.21-3.48).

The absolute risk of probable dementia for CE (0.625 mg) plus MPA (2.5 mg) versus placebo was 45 versus 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).

The most common classification of probable dementia in the treatment group and the placebo group was AD.

Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

The WHIMS estrogen-alone ancillary study of WHI, enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) 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 versus placebo was 1.49 (95 percent CI 0.83-2.66).

The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 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).

The most common classification of probable dementia in both the treatment and placebo groups was AD.

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 percent 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 [see Warnings and Precautions (5.3), and Use in Special Populations (8.5)].

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied PREMPRO therapy consists of a single tablet to be taken once daily.

PREMPRO 0.3 mg/1.5 mg NDC 0046-1105-11, carton includes 1 blister card containing 28 oval, cream tablets.

PREMPRO 0.45 mg/1.5 mg NDC 0046-1106-11, carton includes 1 blister card containing 28 oval, gold tablets.

PREMPRO 0.625 mg/2.5 mg NDC 0046-1107-11, carton includes 1 blister card containing 28 oval, peach tablets.

PREMPRO 0.625 mg/5 mg NDC 0046-0975-06, carton includes 3 EZ DIAL® dispensers each containing 28 oval, light-blue tablets.

NDC 0046-0975-11, carton includes 1 blister card containing 28 oval, light-blue tablets.

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.

NDC 0046–2579–11, carton includes 1 blister card containing 28 tablets (14 oval, maroon Premarin tablets and 14 oval, light-blue tablets).

16.2 Storage and Handling Store at 20° – 25°C (68° – 77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Contraindications (4) 05/2010

GERIATRIC USE

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PREMPRO or PREMPHASE to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE.

The Women’s Health Initiative Study In the Women’s Health Initiative (WHI) estrogen plus progestin substudy (daily conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.6 )].

In the WHI estrogen-alone substudy (daily CE [0.625 mg] versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.6 )].

The Women’s Health Initiative Memory Study In the Women’s Health Initiative Memory Study (WHIMS) of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Clinical Studies (14.7)].

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Clinical Studies (14.7)].

DOSAGE FORMS AND STRENGTHS

3 PREMPRO (conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.3 mg CE plus 1.5 mg MPA oval / cream PREMPRO 0.3/1.5 0.45 mg CE plus 1.5 mg MPA oval / gold PREMPRO 0.45/1.5 0.625 mg CE plus 2.5 mg MPA oval / peach PREMPRO 0.625/2.5 0.625 mg CE plus 5 mg MPA oval / light blue W 0.625/5 PREMPHASE (conjugated estrogens/medroxyprogesterone acetate tablets) Tablet Strength Tablet Shape/Color Imprint 0.625 mg CE oval / maroon (14 tablets) PREMARIN 0.625 0.625 mg CE plus 5 mg MPA oval / light-blue (14 tablets) W 0.625/5 PREMPRO Tablets (not scored): 0.3 mg CE plus 1.5 mg MPA, 0.45 mg CE plus 1.5 mg MPA, 0.625 mg CE plus 2.5 mg MPA, 0.625 mg CE plus 5 mg MPA.

PREMPHASE Tablets (not scored): 0.625 mg CE, 0.625 mg CE plus 5 mg MPA.

MECHANISM OF ACTION

12.1 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 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.

INDICATIONS AND USAGE

1 PREMPRO/PREMPHASE is an estrogen/progestin indicated in women with intact uteri for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1) Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause (1.2) Prevention of Postmenopausal Osteoporosis (1.3) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause 1.3 Prevention of Postmenopausal Osteoporosis

PEDIATRIC USE

8.4 Pediatric Use PREMPRO and PREMPHASE are not indicated in children.

Clinical studies have not been conducted in the pediatric population.

PREGNANCY

8.1 Pregnancy PREMPRO and PREMPHASE should not be used during pregnancy [see Contraindications (4)].

There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

NUSRING MOTHERS

8.3 Nursing Mothers PREMPRO and PREMPHASE should not be used during lactation.

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the breast milk.

Detectable amounts of estrogen and progestin have been identified in the breast milk of mothers receiving these drugs.

Caution should be exercised when PREMPRO or PREMPHASE is administered to a nursing woman.

BOXED WARNING

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.6, 14.7)].

The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.6)].

The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.7)].

Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.6)].

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins.

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.

Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.

Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].

Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.6, 14.7)].

The WHI estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg), relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.6)].

The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.7)].

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.

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.

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA See full prescribing information for complete Boxed Warning.

Estrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism, and myocardial infarction (5.1) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2) 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 (5.3) Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.2) Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3) The WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1) The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gallbladder disease (5.4) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10) Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.18) 5.1 Cardiovascular Disorders An increased risk of pulmonary embolism, deep vein thrombosis (DVT), stroke and myocardial infarction has been reported with estrogen plus progestin therapy.

An increased risk of stroke and DVT has been reported with estrogen-alone therapy.

Should any of these occur or be suspected, estrogens with or without progestins should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history of venous thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be managed appropriately.

Stroke In the Women’s Health Initiative (WHI) estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in all women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies (14.6)].

The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years).

The increase in risk was demonstrated in year one and persisted [see Clinical Studies (14.6)].

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).1 Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.6)].

In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2 [see Clinical Studies ( 14.6 )].

Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1 In postmenopausal women with documented heart disease (n = 2,763), average age 66.7 years, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit.

During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease.

There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during subsequent years.

Two thousand, three hundred and twenty-one (2,321) 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 CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall.

Venous Thromboembolism (VTE) In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years).

Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated.

The increase in VTE risk was demonstrated during the first year and persisted3 [see Clinical Studies ( 14.6 )].

Should a VTE occur or be suspected, estrogens should be discontinued immediately.

In the WHI estrogen-alone substudy, the risk of VTE (DVT and pulmonary embolism [PE]) was increased for women receiving daily CE (0.625 mg) compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years).

The increase in VTE risk was demonstrated during the first 2 years4 [see Clinical Studies ( 14.6 )].

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.

5.2 Malignant Neoplasms Endometrial Cancer Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1 percent or less with PREMPRO or PREMPHASE.

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus.

The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose.

Most studies show no significant increased risk associated with use of estrogens for less than 1 year.

The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 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 using estrogen-alone or estrogen plus progestin therapy is important.

There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast Cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg) plus MPA (2.5 mg).

After a mean follow-up of 5.6 years, the estrogen plus progestin WHI substudy reported an increased risk of breast cancer in women who took daily CE plus MPA.

In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.

The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo.5 Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for estrogen plus progestin compared with placebo.

Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo.

In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group.

Metastatic disease was rare, with no apparent difference between the two groups.

Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups [see Clinical Studies (14.6)].

The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg).

In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg) was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] 6 [see Clinical Studies ( 14.6 )].

Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use.

The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping).

Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy.

However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations.

In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer.

After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI 0.77-3.24).

The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic studies, the use of estrogen-plus progestin and estrogen-only products has been associated with an increased risk of ovarian cancer over multiple years of use.

However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association.

5.3 Probable Dementia In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

In the WHIMS estrogen plus progestin ancillary study, after an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia.

The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent nCI 1.21-3.48).

The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.7)].

In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg) or placebo.

In the WHIMS estrogen-alone ancillary study, after an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia.

The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent nCI 0.83-2.66).

The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.7)].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent nCI 1.19-2.60).

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.7)].

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

5.5 Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women 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.

5.6 Visual Abnormalities Retinal vascular thrombosis has been reported in women 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 permanently discontinued.

5.7 Addition of a Progestin When a Woman Has Not Had a Hysterectomy 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 to estrogen-alone regimens.

These include an increased risk of breast cancer.

5.8 Elevated Blood Pressure 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.

5.9 Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis.

Consider discontinuation of treatment if pancreatitis occurs.

5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with impaired liver function.

For women 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.

5.11 Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.

Women 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.

Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy.

These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

5.12 Fluid Retention Estrogens plus progestins may cause some degree of fluid retention.

Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

5.13 Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

5.14 Exacerbation of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.

For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

5.15 Angioedema Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

5.16 Exacerbation of Other Conditions Estrogen therapy 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.

5.17 Laboratory Tests Serum follicle stimulating hormone and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

5.18 Drug-Laboratory Test Interactions 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 antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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.

Women on thyroid replacement therapy may require higher doses of thyroid hormone.

Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively.

Free hormone concentrations, such as testosterone and estradiol, may be decreased.

Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

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

Impaired glucose tolerance.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See Section 17.4 for FDA-Approved Patient Labeling.

17.1 Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].

17.2 Possible Serious Adverse Reactions With Estrogen Plus Progestin Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3)].

17.3 Possible Less Serious But Common Adverse Reactions With Estrogen Plus Progestin Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.

17.4 FDA-Approved Patient Labeling

DOSAGE AND ADMINISTRATION

2 PREMPRO: one tablet containing conjugated estrogens (CE) plus medroxyprogesterone acetate (MPA) taken orally once daily (2).

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 (2).

2.1 General Dosing Information Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.

Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

2.2 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause PREMPRO therapy consists of a single tablet to be taken orally once daily.

PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg Premarin (conjugated estrogens) 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.

2.3 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause PREMPRO therapy consists of a single tablet to be taken orally once daily.

PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg Premarin [conjugated estrogens (CE)] tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg of medroxyprogesterone acetate (MPA) taken on days 15 through 28.

When prescribing solely for the treatment of moderate to severe vulvar and vaginal atrophy, topical vaginal products should be considered.

2.4 Prevention of Postmenopausal Osteoporosis PREMPRO therapy consists of a single tablet to be taken orally once daily.