PREMARIN 0.625 MG Oral Tablet

Details

Generic Name: CONJUGATED ESTROGENS

Brand Name: Premarin

Substance Name(s):
ESTROGENS, CONJUGATED

WARNINGS

See BOXED .

Cardiovascular disorders An increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen alone therapy.

An increased risk of stroke, DVT, pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy.

Should any of these events 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 or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Stroke In the Women’s Health Initiative (WHI) estrogen alone substudy, a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) compared to placebo (44 versus 32 per 10,000 women-years).

The increase in risk was demonstrated in year one and persisted.

(See CLINICAL STUDIES .) In the estrogen plus progestin substudy of WHI, a statistically significant increased risk of stroke was reported in women receiving daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo (31 versus 24 per 10,000 women-years).

The increase in risk was demonstrated after the first year and persisted.

(See CLINICAL STUDIES .) b.

Coronary heart disease In the estrogen alone substudy of WHI, 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 placebo.

(See CLINICAL STUDIES .) In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to placebo (39 versus 33 per 10,000 women years).

An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.

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/MPA 2.5 mg demonstrated no cardiovascular benefit.

During an average follow-up of 4.1 years, treatment with CE/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/MPA-treated group than in the placebo group in year one, but not during the 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/MPA group and the placebo group in the HERS, the HERS II, and overall.

Venous thromboembolism (VTE) In the estrogen alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women receiving daily CE 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 years.

(See CLINICAL STUDIES .) In the estrogen plus progestin substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE/MPA compared to 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 persisted.

(See 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 a.

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

The reported endometrial cancer risk among unopposed estrogen users with an intact uterus is about 2 to 12 times greater than in non-users, 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 1 year.

The greatest risk appears 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 plus progestin therapy 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.

Adding a progestin to postmenopausal estrogen therapy 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 this issue in estrogen alone users is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg).

In the estrogen alone substudy of WHI, after an average 7.1 years of follow-up, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62-1.04).

(see CLINICAL STUDIES ).

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

In the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/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 (95 percent nCI 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively.

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 CE/MPA 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/MPA 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 .) The results from observational studies are generally consistent with those of the WHI clinical trial.

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.

Dementia In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily conjugated estrogens (CE 0.625 mg) or placebo.

In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo.

In the estrogen alone substudy, 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 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.

(See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use .) In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia.

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

The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years.

(See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use .) 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).

Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

(See BOXED and PRECAUTIONS, Geriatric Use .) 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.

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 permanently discontinued.

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

DRUG INTERACTIONS

Drug Interactions Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are 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.

OVERDOSAGE

Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females.

Treatment of overdose consists of discontinuation of PREMARIN together with institution of appropriate symptomatic care.

DESCRIPTION

PREMARIN® (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares’ urine.

It is a mixture of sodium estrone sulfate and sodium equilin sulfate.

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

Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of conjugated estrogens.

PREMARIN 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, carnauba wax, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, powdered cellulose, sucrose, and titanium dioxide.

— 0.3 mg tablets also contain: D&C Yellow No.

10 and FD&C Blue No.

— 0.45 mg tablets also contain: FD&C Blue No.

— 0.625 mg tablets also contain: FD&C Blue No.

2 and FD&C Red No.

40.

— 0.9 mg tablets also contain: D&C Red No.

30 and D&C Red No.

— 1.25 mg tablets also contain: black iron oxide, D&C Yellow No.

10 and FD&C Yellow No.

PREMARIN tablets comply with USP Dissolution Test criteria as outlined below: PREMARIN 1.25 mg tablets USP Dissolution Test 4 PREMARIN 0.3 mg, 0.45 mg and 0.625 mg tablets USP Dissolution Test 5 PREMARIN 0.9 mg tablets USP Dissolution Test 6

CLINICAL STUDIES

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, receiving either placebo or conjugated estrogens, with or without medroxyprogesterone acetate.

Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization.

PREMARIN (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms.

Table 2 shows the adjusted mean number of hot flushes in the PREMARIN 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.

TABLE 2.

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) Treatment (No.

of Patients) ——————-No.

of Hot Flushes/Day—————— a: Based on analysis of covariance with treatment as factor and baseline as covariate.

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

Placeboa 0.625 mg CE (n = 27) 4 12 12.29 ± 3.89 12.29 ± 3.89 1.95 ± 2.77 0.75 ± 1.82 -10.34 ± 4.73 -11.54 ± 4.62 <0.001 <0.001 0.45 mg CE (n = 32) 4 12 12.25 ± 5.04 12.25 ± 5.04 5.04 ± 5.31 2.32 ± 3.32 -7.21 ± 4.75 -9.93 ± 4.64 <0.001 <0.001 0.3 mg CE (n = 30) 4 12 13.77 ± 4.78 13.77 ± 4.78 4.65 ± 3.71 2.52 ± 3.23 -9.12 ± 4.71 -11.25 ± 4.60 <0.001 <0.001 Placebo (n = 28) 4 12 11.69 ± 3.87 11.69 ± 3.87 7.89 ± 5.28 5.71 ± 5.22 -3.80 ± 4.71 -5.98 ± 4.60 – – Effects on vulvar and vaginal atrophy Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p < 0.001) for all treatment groups (conjugated estrogens alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).

Effects on bone mineral density 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 PREMARIN 0.625 mg, 0.45 mg, 0.3 mg, or placebo.

Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4).

Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed.

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 at cycles 6, 13, 19, and 26.

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 2.46 percent with 0.625 mg, 2.26 percent with 0.45 mg, and 1.13 percent with 0.3 mg.

The placebo group showed a mean percent decrease from baseline at the final evaluation of 2.45 percent.

These results show that the lower dosages of PREMARIN were effective in increasing L2 to L4 BMD compared with placebo, and therefore support the efficacy of the lower doses.

The analysis for the other three 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 PREMARIN treatments was more effective than placebo for all three of these additional BMD endpoints.

With regard to femoral neck and total body, the active treatment groups all showed mean percent increases in BMD, while placebo treatment was accompanied by mean percent decreases.

For femoral trochanter, each of the PREMARIN dose 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 3.

TABLE 3.

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) of PREMARIN or placebo.

L2 to L4 BMD 0.625 0.45 0.3 Placebo 83 91 87 85 1.17 ± 0.15 1.13 ± 0.15 1.14 ± 0.15 1.14 ± 0.14 2.46 ± 0.37 2.26 ± 0.35 1.13 ± 0.36 -2.45 ± 0.36 <0.001 <0.001 <0.001 Total Body BMD 0.625 0.45 0.3 Placebo 84 91 87 85 1.15 ± 0.08 1.14 ± 0.08 1.14 ± 0.07 1.13 ± 0.08 0.68 ± 0.17 0.74 ± 0.16 0.40 ± 0.17 -1.50 ± 0.17 <0.001 <0.001 <0.001 Femoral Neck BMD 0.625 0.45 0.3 Placebo 84 91 87 85 0.91 ± 0.14 0.89 ± 0.13 0.86 ± 0.11 0.88 ± 0.14 1.82 ± 0.45 1.84 ± 0.44 0.62 ± 0.45 -1.72 ± 0.45 <0.001 <0.001 <0.001 Femoral Trochanter BMD 0.625 0.45 0.3 Placebo 84 91 87 85 0.78 ± 0.13 0.76 ± 0.12 0.75 ± 0.10 0.75 ± 0.12 3.82 ± 0.58 3.16 ± 0.56 3.05 ± 0.57 0.81 ± 0.58 <0.001 0.003 0.005 Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater than the value shown on the x-axis.

Figure 1.

CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN® AND PLACEBO GROUPS The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 2.

Significant differences between each of the PREMARIN dosage groups and placebo were found at cycles 6, 13, 19, and 26.

Figure 2.

ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN® GROUPS AND PLACEBO The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (p < 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group.

Larger mean decreases from baseline were seen with the active groups than with the placebo group.

Significant differences from placebo were seen less frequently in urine calcium.

Figure 1 Figure 2 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 either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (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] (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 CE/MPA substudy),colorectal cancer, hip fracture, or death due to other causes.

The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The 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 6.8 years, are presented in Table 4.

TABLE 4.

RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHI Event Relative Risk CE vs.

Placebo (95% nCIa) Placebo n = 5,429 CE n = 5,310 Absolute Risk per 10,000 Women-Years aNominal confidence intervals unadjusted for multiple looks and multiple comparisons.

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

cResults are based on an average follow-up of 6.8 years.

dNot included in Global Index.

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

fA 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.

CHD eventsb 0.95 (0.79-1.16) 56 53 Non-fatal MI b 0.91 (0.73-1.14) 43 40 CHD death b 1.01 (0.71-1.43) 16 16 Strokeb 1.37 (1.09-1.73) 33 45 Ischemic b 1.55 (1.19-2.01) 25 38 Deep vein thrombosisb,d 1.47 (1.06-2.06) 15 23 Pulmonary embolismb 1.37 (0.90-2.07) 10 14 Invasive breast cancerb 0.80 (0.62-1.04) 34 28 Colorectal cancerc 1.08 (0.75-1.55) 16 17 Hip fracturec 0.61 (0.41-0.91) 17 11 Vertebral fracturesc,d 0.62 (0.42-0.93) 17 11 Total fracturesc,d 0.70 (0.63-0.79) 195 139 Death due to other causesc,e 1.08 (0.88-1.32) 50 53 Overall mortalityc,d 1.04 (0.88-1.22) 78 81 Global Indexc,f 1.01 (0.91-1.12) 190 192 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 were 12 more strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures.

The absolute excess risk of events included in the “global index” was a nonsignificant 2 events per 10,000 women-years.

There was no difference between the groups in terms of all-cause mortality.

(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS .) Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen alone substudy, after an average follow-up of 7.1 years, reported 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 (see Table 4).

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 of ischemic stroke, and this excess was present in all subgroups of women examined (see Table 4).

The estrogen plus progestin substudy was also stopped early.

According to the predefined stopping rule, after an average follow-up of 5.2 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 (relative risk [RR] 1.15, 95 percent nCI 1.03-1.28).

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/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures.

(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS .) Results of the estrogen plus progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 5.

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

TABLE 5.

RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa Event Relative Risk CE/MPA vs.

Placebo (95% nCIb) Placebo n = 8,102 CE/MPA n = 8,506 Absolute Risk per 10,000 Women-years aResults are based on centrally adjudicated data.

Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95 percent nCI 0.82-1.18).

bNominal confidence intervals unadjusted for multiple looks and multiple comparisons.

cIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.

CHD events 1.24 (1.00-1.54) 33 39 Non-fatal MI 1.28 (1.00-1.63) 25 31 CHD death 1.10 (0.70-1.75) 8 8 All strokes 1.31 (1.02-1.68) 24 31 Ischemic Stroke 1.44 (1.09-1.90) 18 26 Deep vein thrombosis 1.95 (1.43-2.67) 13 26 Pulmonary embolism 2.13 (1.45-3.11) 8 18 Invasive breast cancerc 1.24 (1.01-1.54) 33 41 Invasive colorectal cancer 0.56 (0.38-0.81) 16 9 Endometrial cancer 0.81 (0.48-1.36) 7 6 Cervical cancer 1.44 (0.47-4.42) 1 2 Hip fracture 0.67 (0.47-0.96) 16 11 Vertebral fractures 0.65 (0.46-0.92) 17 11 Lower arm/wrist fractures 0.71 (0.59-0.85) 62 44 Total fractures 0.76 (0.69-0.83) 199 152 Women’s Health Initiative Memory Study The estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent, age 65 to 69 years; 36 percent, 70 to 74 years; 19 percent, 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 with placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia.

The relative risk of probable dementia in the estrogen alone group was 1.49 (95 percent CI 0.83–2.66) compared to placebo.

It is unknown whether these findings apply to younger postmenopausal women.

(See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use .) The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent, age 65 to 69 years; 35 percent, 70 to 74 years; 18 percent, 75 years of age and older) to evaluate the effects of CE/MPA 0.625 mg conjugated estrogens/2.5 mg medroxyprogesterone acetate daily on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen plus progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia.

The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI 1.21–3.48) compared to placebo.

It is unknown whether these findings apply to younger postmenopausal women.

(See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use .) 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 BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use .)

HOW SUPPLIED

PREMARIN® (conjugated estrogens tablets, USP) — Each oval green tablet contains 0.3 mg.

— Each oval blue tablet contains 0.45 mg.

— Each oval maroon tablet contains 0.625 mg.

— Each oval white tablet contains 0.9 mg.

— Each oval yellow tablet contains 1.25 mg.

The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.

They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod.

Code 53808-0770-1 0.625 mg 30 Tablets in a Blister Pack MAROON 0046-1102 Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Dispense in a well-closed container, as defined in the USP.

GERIATRIC USE

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

In the estrogen alone substudy of the Women’s Health Initiative (WHI) study, 46 percent (n=4,943) were 65 years of age and older, while 7.1 percent (n=767) were 75 years of age and older.

There was a higher relative risk (daily conjugated estrogens [CE 0.625 mg] versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older.

In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy 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.

After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI 0.83-2.66).

The absolute risk of developing probable dementia with estrogen alone was 37 versus 25 cases per 10,000 women-years compared with placebo.

Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health Initiative study, 44 percent (n=7,320) were 65 years of age and older, while 6.6 percent (n=1,095) were 75 years and older.

In women 75 years of age and older compared to women less than 74 years of age, there was a higher relative risk of nonfatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo.

In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women years, respectively.

In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal women, 65 to 79 years of age, was randomized to daily CE 0.625 mg/MPA 2.5 mg or placebo.

In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI 1.21-3.48).

The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.

Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group.

The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer’s disease.

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).

Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

(See BOXED WARNINGS and WARNINGS, Dementia .)

INDICATIONS AND USAGE

PREMARIN therapy is indicated in the: Treatment of moderate to severe vasomotor symptoms due to menopause.

Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

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

Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.

Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.

Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).

Prevention of postmenopausal osteoporosis.

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.

(See CLINICAL STUDIES .)The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy.

Postmenopausal women require an average of 1500 mg/day of elemental calcium.

Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake.

Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

PEDIATRIC USE

Pediatric Use Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay.

Safety and effectiveness in pediatric patients have not otherwise been established.

Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children.

If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.

Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding.

In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia.

(See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION .)

PREGNANCY

Pregnancy PREMARIN should not be used during pregnancy.

(See CONTRAINDICATIONS .)

NUSRING MOTHERS

Nursing Mothers PREMARIN should not be used during lactation.

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

Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.

BOXED WARNING

WARNINGS ENDOMETRIAL CANCER 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.

(See WARNINGS, Malignant neoplasms, Endometrial cancer .) CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia.

(See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia .) The estrogen alone substudy of the Women’s Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with daily oral conjugated estrogens (CE 0.625 mg), relative to placebo.

(See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders .) The estrogen plus progestin substudy of WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo.

(See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer .) The Women’s Health Initiative Memory Study (WHIMS), a substudy 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 and 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 CLINICAL STUDIES and WARNINGS, Dementia and PRECAUTIONS, Geriatric Use .) 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.

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.

INFORMATION FOR PATIENTS

Patient Information Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMARIN.

DOSAGE AND ADMINISTRATION

When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer.

A woman without a uterus does not need progestin.

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.

Patients should be reevaluated periodically as clinically appropriate (for example at 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS ).

For women with 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.

PREMARIN may be taken without regard to meals.