ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER

Close clinical surveillance of all women taking estrogens 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. (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 WARNINGS , Cardiovascular disorders and Dementia .)

The Women's Health Initiative (WHI) study reported increased risks of stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with conjugated estrogens (0.625 mg) relative to placebo. (See CLINICAL PHARMACOLOGY , Clinical Studies and WARNINGS , Cardiovascular disorders .)

The WHI study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY , Clinical Studies and WARNINGS , Cardiovascular disorders and Malignant neoplasms , Breast cancer .)

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with conjugated estrogens alone and during 4 years of treatment with conjugated estrogens combined with medroxyprogesterone acetate, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY , Clinical Studies , WARNINGS , Dementia and PRECAUTIONS , Geriatric Use .)

Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

DESCRIPTION

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, 17(alpha)-dihydroequilin, 17(alpha)-estradiol, and 17(beta)-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, and 0.9 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, microcrystalline cellulose, powdered cellulose, glyceryl monooleate, lactose monohydrate, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid (not present in 0.45 mg tablet), sucrose, and titanium dioxide.

Premarin 1.25 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, and titanium dioxide.

Premarin tablets comply with USP Drug Release Test criteria as outlined below:

Premarin 0.3 mg, 0.45 mg, Test 1
and 0.625 mg tablets  
Premarin 0.9 mg tablets Test 2
Premarin 1.25 mg tablets USP Drug Release Test pending

CLINICAL PHARMACOLOGY

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.

Pharmacokinetics

Absorption

Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Premarin tablet releases conjugated estrogens slowly over several hours. Table 1 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens following administration of 2 × 0.3 mg, 2 × 0.45 mg, and 2 × 0.625 mg tablets to healthy postmenopausal women.

TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 × 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(pg/mL)
t max
(h)
t 1/2
(h)
AUC
(pg·h/mL)
82 (33) 7.8 (27) 54.7 (42) 5390 (50)
Baseline-adjusted estrone
58 (42) 7.8 (27) 21.1 (45) 1467 (41)
31 (47) 7.2 (28) 18.3 (110) 652 (68)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 × 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(ng/mL)
t max
(h)
t 1/2
(h)
AUC
(ng·h/mL)
2.5 (32) 6.5 (29) 25.4 (22) 61.0 (43)
Baseline-adjusted total estrone
2.4 (32) 6.5 (29) 16.2 (34) 40.8 (36)
1.6 (40) 5.9 (27) 11.8 (21) 22.4 (42)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 × 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(pg/mL)
t max
(h)
t 1/2
(h)
AUC
(pg·h/mL)
92 (32) 8.7 (28) 56.4 (68) 6344 (56)
Baseline-adjusted estrone
65 (40) 8.7 (28) 20.3 (38) 1940 (40)
35 (49) 7.6 (33) 21.9 (113) 849 (60)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 × 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(ng/mL)
t max
(h)
t 1/2
(h)
AUC
(ng·h/mL)
Total estrone
2.8 (46) 7.1 (27) 27.6 (35) 77 (34)
Baseline-adjusted total estrone
2.6 (46) 7.1 (27) 14.7 (42) 48 (38)
Total equilin
1.9 (53) 5.9 (32) 11.8 (32) 29 (55)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 × 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(pg/mL)
t max
(h)
t 1/2
(h)
AUC
(pg·h/mL)
139 (37) 8.8 (20) 28.0 (30) 5016 (34)
Baseline-adjusted estrone
120 (41) 8.8 (20) 17.4 (37) 2956 (39)
66 (42) 7.9 (19) 13.6 (52) 1210 (37)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 × 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(ng/mL)
t max
(h)
t 1/2
(h)
AUC
(ng·h/mL)
Total estrone
7.3 (41) 7.3 (24) 15.0 (25) 134 (42)
Baseline-adjusted total estrone
7.1 (41) 7.3 (24) 13.6 (23) 122 (38)
Total equilin
5.0 (42) 6.2 (26) 10.1 (26) 65 (44)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(pg/mL)
t max
(h)
t 1/2
(h)
AUC
(pg·h/mL)
124 (30) 10.0 (32) 38.1 (37) 6332 (44)
Baseline-adjusted estrone
102 (35) 10.0 (32) 19.7 (48) 3159 (53)
59 (43) 8.8 (36) 10.9 (47) 1182 (42)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 × 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
C max
(ng/mL)
t max
(h)
t 1/2
(h)
AUC
(ng·h/mL)
Total Estrone
4.5 (39) 8.2 (58) 26.5 (40) 109 (46)
Baseline-adjusted total estrone
4.3 (41) 8.2 (58) 17.5 (41) 87 (44)
Total equilin
2.9 (42) 6.8 (49) 12.5 (34) 48 (51)

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

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

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Special Populations

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

Drug Interactions

Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic 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.

Clinical Studies

Effects on vasomotor symptoms.

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups, 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 7 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, LOCF
Treatment
(No. of Patients)
-------------------------No. of Hot Flushes/Day------------------------- p-Values
vs. Placebo a
Time Period
(week)
Baseline
Mean ± SD
Observed
Mean ± SD
Mean
Change± SD
0.625 mg CE
(n = 27)
     4
12.29 ± 3.89 1.95 ± 2.77 -10.34 ± 4.73 <0.001
     12
12.29 ± 3.89 0.75 ± 1.82 -11.54 ± 4.62 <0.001
0.45 mg CE
(n = 32)
     4
12.25 ± 5.04 5.04 ± 5.31 -7.21 ± 4.75 <0.001
     12
12.25 ± 5.04 2.32 ± 3.32 -9.93 ± 4.64 <0.001
0.3 mg CE
(n = 30)
     4
13.77 ± 4.78 4.65 ± 3.71 -9.12 ± 4.71 <0.001
     12
13.77 ± 4.78 2.52 ± 3.23 -11.25 ± 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 --
a: Based on analysis of covariance with treatment as factor and baseline as covariate.

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 (L 2 to L 4 ). 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 4 BMD endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy measure (L 2 to L 4 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% with 0.625 mg, 2.26% with 0.45 mg, and 1.13% with 0.3 mg. The placebo group showed a mean percent decrease from baseline at the final evaluation of 2.45%. These results show that the lower dosages of Premarin were effective in increasing L 2 to L 4 BMD compared with placebo and, therefore, support the efficacy of the lower doses.

The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral trochanter that were generally larger than those seen for L 2 to L 4 and changes in femoral neck and total body that were generally smaller than those seen for L 2 to L 4 . Significant differences between groups indicated that each of the Premarin treatments was more effective than placebo for all 3 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,
LAST OBSERVATION CARRIED FORWARD
Region Evaluated
     Treatment Group a
No. of
Subjects
Baseline (g/cm 2 )
Mean ± SD
Change from Baseline (%)
Adjusted Mean ± SE
p-Value vs
Placebo
L 2 to L 4 BMD
     0.625
83 1.17 ± 0.15 2.46 ± 0.37 <0.001
     0.45
91 1.13 ± 0.15 2.26 ± 0.35 <0.001
     0.3
87 1.14 ± 0.15 1.13 ± 0.36 <0.001
     Placebo
85 1.14 ± 0.14 -2.45 ± 0.36  
Total Body BMD
     0.625
84 1.15 ± 0.08 0.68 ± 0.17 <0.001
     0.45
91 1.14 ± 0.08 0.74 ± 0.16 <0.001
     0.3
87 1.14 ± 0.07 0.40 ± 0.17 <0.001
     Placebo
85 1.13 ± 0.08 -1.50 ± 0.17  
     0.625
84 0.91 ± 0.14 1.82 ± 0.45 <0.001
     0.45
91 0.89 ± 0.13 1.84 ± 0.44 <0.001
     0.3
87 0.86 ± 0.11 0.62 ± 0.45 <0.001
     Placebo
85 0.88 ± 0.14 -1.72 ± 0.45  
     0.625
84 0.78 ± 0.13 3.82 ± 0.58 <0.001
     0.45
91 0.76 ± 0.12 3.16 ± 0.56 0.003
     0.3
87 0.75 ± 0.10 3.05 ± 0.57 0.005
     Placebo
85 0.75 ± 0.12 0.81 ± 0.58  
a: Identified by dosage (mg) of Premarin or placebo.

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

images/79/04061601.jpg

The mean percent changes from baseline in L 2 to L 4 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.

images/79/04061602.jpg

The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (p<0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium.

Women's Health Initiative Studies.

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

The 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% White, 15% Black, 6.1% Hispanic), after an average follow-up of 6.8 years are presented in Table 4 below.

TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHI a
Event c Relative Risk *
Premarin vs Placebo
at 6.8 Years
(95% CI)
Placebo
n = 5429
Premarin
n = 5310
Absolute Risk per 10,000 Women-years
CHD events
0.91 (0.75-1.12) 54 49
      Non-fatal MI
0.89 (0.70-1.12) 41 37
      CHD death
0.94 (0.65-1.36) 16 15
0.77 (0.59-1.01) 33 26
1.39 (1.10-1.77) 32 44
1.34 (0.87-2.06) 10 13
1.08 (0.75-1.55) 16 17
Hip fracture
0.61 (0.41-0.91) 17 11
Death due to other causes than the
events above
1.08 (0.88-1.32) 50 53
1.01 (0.91-1.12) 190 192
 
1.47 (1.04-2.08) 15 21
0.62 (0.42-0.93) 17 11
0.70 (0.63-0.79) 195 139
a:adapted from JAMA, 2004; 291:1701-1712
b:a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
c:not included in Global Index
*nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

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 Premarin 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 .)

The estrogen plus progestin substudy was also stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the estrogen plus progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below.

TABLE 5. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI a
Event c Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI * )
Placebo
n = 8102
Prempro
n = 8506
Absolute Risk per 10,000 Women-years
CHD events
1.29 (1.02-1.63) 30 37
   Non-fatal MI
1.32 (1.02-1.72) 23 30
   CHD death
1.18 (0.70-1.97) 6 7
1.26 (1.00-1.59) 30 38
1.41 (1.07-1.85) 21 29
2.13 (1.39-3.25) 8 16
0.63 (0.43-0.92) 16 10
0.83 (0.47-1.47) 6 5
Hip fracture
0.66 (0.45-0.98) 15 10
Death due to causes other than the
events above
0.92 (0.74-1.14) 40 37
1.15 (1.03-1.28) 151 170
 
2.07 (1.49-2.87) 13 26
0.66 (0.44-0.98) 15 9
0.77 (0.69-0.86) 170 131
a:adapted from JAMA, 2002; 288:321-333
b:includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c:a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
d:not included in Global Index
*nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

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

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% were age 65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to evaluate the effects of Premarin (0.625 mg conjugated estrogens) 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% CI, 0.83 to 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% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/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% CI, 1.21 to 3.48) compared to placebo. 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 .)

INDICATIONS AND USAGE

Premarin therapy is indicated in the:

  1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
  2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
  3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
  4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
  5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
  6. 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 PHARMACOLOGY , 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.

CONTRAINDICATIONS

Estrogens should not be used in individuals with any of the following conditions:

  1. Undiagnosed abnormal genital bleeding.
  2. Known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.
  3. Known or suspected estrogen-dependent neoplasia.
  4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
  5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
  6. Liver dysfunction or disease.
  7. Premarin tablets should not be used in patients with known hypersensitivity to their ingredients.
  8. Known or suspected pregnancy. There is no indication for Premarin in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogen and progestins from oral contraceptives inadvertently during pregnancy. (See PRECAUTIONS .)

WARNINGS

See BOXED WARNINGS .

1. Cardiovascular disorders. Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

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

  1. Coronary heart disease and stroke. In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of stroke was observed in women receiving Premarin (0.625 mg conjugated estrogens) per day compared to women receiving placebo (44 vs 32 per 10,000 women-years). The increase in risk was observed in year one and persisted. (See CLINICAL PHARMACOLOGY , Clinical Studies .)
    In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.
    In the same estrogen plus progestin substudy of WHI, an increased risk of stroke was observed in women receiving PREMPRO compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.
    In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the PREMPRO-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the PREMPRO group and the placebo group in HERS, HERS II, and overall.
    Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
  2. Venous thromboembolism (VTE). In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving Premarin compared to placebo (21 vs 15 per 10,000 women-years). The increase in VTE risk was observed during the first year. (See CLINICAL PHARMACOLOGY , Clinical Studies .)
    In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.
    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.

2. Malignant neoplasms.

a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users with an intact uterus is about 2- to 12-fold 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 one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. 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.

b. Breast cancer. In some studies, the use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) trial of estrogen plus progestin (see CLINICAL PHARMACOLOGY , Clinical Studies ). The results from observational studies are generally consistent with those of the WHI clinical trial.

After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in women who took estrogen plus progestin. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen/progestin combinations, doses, or routes of administration.

In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. 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 vs. 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 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen plus progestin 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.

The observational Million Women Study in Europe reported an increased risk of mortality due to breast cancer among current users of estrogens alone or estrogens plus progestins compared to never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast cancer mortality with a mean follow-up of 5.6 years.

The use of 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.

3. Dementia. In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to Premarin (0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to PREMPRO (0.625 mg/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 Premarin alone versus placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for Premarin alone versus placebo was 37 versus 25 cases per 10,000 women-years.

In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin versus placebo was 2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for PREMPRO versus placebo was 45 versus 22 cases per 10,000 women-years.

Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS 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.

5. 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.

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

PRECAUTIONS

A. General

  1. 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: a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of glucose tolerance.
  2. 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. Blood pressure should be monitored at regular intervals during estrogen use.
  3. Hypertriglyceridemia.
    In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with Premarin 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were 34.3, 30.2, 25.1, and 10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0, and 5.5, respectively.
  4. Impaired liver function and past history of cholestatic jaundice.
    Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
  5. Hypothyroidism.
    Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T 4 and T 3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
  6. Fluid retention.
    Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
  7. Hypocalcemia.
    Estrogens should be used with caution in individuals with severe hypocalcemia.
  8. Ovarian cancer.
    The estrogen plus progestin substudy of WHI reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% confidence interval 0.77 - 3.24) but was not statistically significant. The absolute risk of estrogen plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
  9. Exacerbation of endometriosis.
    Endometriosis may be exacerbated with administration of estrogen therapy.
    A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
  10. 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 patients with these conditions.

B. Patient Information

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

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose for the treatment of postmenopausal moderate to severe vasomotor symptoms and moderate to severe symptoms of postmenopausal vulvar and vaginal atrophy and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH). Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.

D. Drug/Laboratory Test Interactions

  1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
  2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
  3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
  4. Increased plasma HDL and HDL 2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.
  5. Impaired glucose tolerance.
  6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

(See BOXED WARNINGS , WARNINGS , and PRECAUTIONS .)

Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

F. Pregnancy

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

G. Nursing Mothers

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

H. Pediatric Use

Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.

Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.

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

I. Geriatric Use

Of the total number of subjects in the estrogen alone substudy of the Women's Health Initiative (WHI) study, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and over. There was a higher relative risk (Premarin vs. placebo) of stroke in women less than 75 years of age compared to women 75 years and over.

In the estrogen alone substudy of the Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to Premarin (0.625 mg) or placebo. In the estrogen alone group, after an average follow-up of 5.2 years, the relative risk (Premarin versus placebo) of probable dementia was 1.49 (95% CI 0.83-2.66).

Of the total number of subjects in the estrogen plus progestin substudy of the Women's Health Initiative study, 44% (n=7,320) were 65 years and over, while 6.6% (n=1,095) were 75 years and over. There was a higher relative risk (PREMPRO vs placebo) of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age.

In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomized to PREMPRO (0.625 mg/2.5 mg) or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (PREMPRO versus placebo) of probable dementia was 2.05 (95% CI 1.21-3.48).

Pooling the events in women receiving Premarin or PREMPRO in comparison to those in women on placebo, the overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS , Dementia .)

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.

ADVERSE REACTIONS

See BOXED WARNINGS , WARNINGS , and PRECAUTIONS .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65 years of age (88% Caucasian), 1012 women were treated with conjugated estrogens and 332 were treated with placebo. Table 6 summarizes adverse events that occurred at a rate of >/= 5%.

TABLE 6. NUMBER (%) OF PATIENTS REPORTING >/= 5% TREATMENT EMERGENT ADVERSE EVENTS
Body System
    Adverse event
--Conjugated Estrogens Treatment Group-- Placebo
(n = 332)
0.625 mg
(n = 348)
0.45 mg
(n = 338)
0.3 mg
(n = 326)
Any adverse event
323 (93%) 305 (90%) 292 (90%) 281 (85%)
Body as a Whole
     Abdominal pain
56 (16%) 50 (15%) 54 (17%) 37 (11%)
     Accidental injury
21 (6%) 41 (12%) 20 (6%) 29 (9%)
     Asthenia
25 (7%) 23 (7%) 25 (8%) 16 (5%)
     Back pain
49 (14%) 43 (13%) 43 (13%) 39 (12%)
     Flu syndrome
37 (11%) 38 (11%) 33 (10%) 35 (11%)
     Headache
90 (26%) 109 (32%) 96 (29%) 93 (28%)
     Infection
61 (18%) 75 (22%) 74 (23%) 74 (22%)
     Pain
58 (17%) 61 (18%) 66 (20%) 61 (18%)
     Diarrhea
21 (6%) 25 (7%) 19 (6%) 21 (6%)
     Dyspepsia
33 (9%) 32 (9%) 36 (11%) 46 (14%)
     Flatulence
24 (7%) 23 (7%) 18 (6%) 9 (3%)
     Nausea
32 (9%) 21 (6%) 21 (6%) 30 (9%)
     Arthralgia
47 (14%) 42 (12%) 22 (7%) 39 (12%)
     Leg cramps
19 (5%) 23 (7%) 11 (3%) 7 (2%)
     Myalgia
18 (5%) 18 (5%) 29 (9%) 25 (8%)
     Depression
25 (7%) 27 (8%) 17 (5%) 22 (7%)
     Dizziness
19 (5%) 20 (6%) 12 (4%) 17 (5%)
     Insomnia
21 (6%) 25 (7%) 24 (7%) 33 (10%)
     Nervousness
12 (3%) 17 (5%) 6 (2%) 7 (2%)
     Cough increased
13 (4%) 22 (7%) 14 (4%) 14 (4%)
     Pharyngitis
35 (10%) 35 (10%) 40 (12%) 38 (11%)
     Rhinitis
21 (6%) 30 (9%) 31 (10%) 42 (13%)
     Sinusitis
22 (6%) 36 (11%) 24 (7%) 24 (7%)
     Upper respiratory infection
42 (12%) 34 (10%) 28 (9%) 35 (11%)
     Pruritus
14 (4%) 17 (5%) 16 (5%) 7 (2%)
     Breast pain
38 (11%) 41 (12%) 24 (7%) 29 (9%)
     Leukorrhea
18 (5%) 22 (7%) 13 (4%) 9 (3%)
     Vaginal hemorrhage
47 (14%) 14 (4%) 7 (2%) 0
     Vaginal moniliasis
20 (6%) 18 (5%) 17 (5%) 6 (2%)
     Vaginitis
24 (7%) 20 (6%) 16 (5%) 4 (1%)

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

  1. Genitourinary system
    Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting, dysmenorrhea
    Increase in size of uterine leiomyomata
    Vaginitis, including vaginal candidiasis
    Change in amount of cervical secretion
    Change in cervical ectropion
    Ovarian cancer
    Endometrial hyperplasia
    Endometrial cancer
  2. Breasts
    Tenderness, enlargement, pain, discharge, galactorrhea
    Fibrocystic breast changes
    Breast cancer
  3. Cardiovascular
    Deep and superficial venous thrombosis
    Pulmonary embolism
    Thrombophlebitis
    Myocardial infarction
    Stroke
    Increase in blood pressure
  4. Gastrointestinal
    Nausea, vomiting
    Abdominal cramps, bloating
    Cholestatic jaundice
    Increased incidence of gallbladder disease
    Pancreatitis
    Enlargement of hepatic hemangiomas
  5. Skin
    Chloasma or melasma that may persist when drug is discontinued
    Erythema multiforme
    Erythema nodosum
    Hemorrhagic eruption
    Loss of scalp hair
    Hirsutism
    Pruritus, rash
  6. Eyes
    Retinal vascular thrombosis
    Intolerance to contact lenses
  7. Central Nervous System
    Headache
    Migraine
    Dizziness
    Mental depression
    Chorea
    Nervousness
    Mood disturbances
    Irritability
    Exacerbation of epilepsy
    Dementia
  8. Miscellaneous
    Increase or decrease in weight
    Reduced carbohydrate tolerance
    Aggravation of porphyria
    Edema
    Arthralgias
    Leg cramps
    Changes in libido
    Urticaria, angioedema, anaphylactoid/anaphylactic reactions
    Hypocalcemia
    Exacerbation of asthma
    Increased triglycerides

OVERDOSAGE

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

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 re-evaluated periodically as clinically appropriate (e.g., 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.

  1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
    Patients should be treated with the lowest effective dose. Generally women should be started at 0.3 mg Premarin daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider.
    Premarin therapy may be given continuously with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug) as is medically appropriate on an individualized basis.
  2. For prevention of postmenopausal osteoporosis:
    When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. Patients should be treated with the lowest effective dose. Generally women should be started at 0.3 mg Premarin daily. Subsequent dosage adjustment may be made based upon the individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider.
    Premarin therapy may be given continuously with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug) as is medically appropriate on an individualized basis.
  3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure:
    Female hypogonadism--0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium.
    In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12 month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios of bone age advancement to chronological age progression ((DELTA)BA/(DELTA)CA) of 1.1, 1.5, and 2.1, respectively. (Premarin in the dose strength of 0.15 mg is not available commercially). Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.
    Female castration or primary ovarian failure--1.25 mg daily, cyclically. Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control.
  4. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease:
    Suggested dosage is 10 mg three times daily for a period of at least three months.
  5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
    1.25 mg to 2 × 1.25 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

HOW SUPPLIED

Premarin (conjugated estrogens tablets, USP)

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

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.

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.

images/pills/p06337a3.jpg

PATIENT INFORMATION

(Updated April 2005)

Premarin ®

(conjugated estrogens tablets, USP)

Read this PATIENT INFORMATION before you start taking Premarin and read what you get each time you refill Premarin. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Premarin (an estrogen mixture)?

What is Premarin?

Premarin is a medicine that contains a mixture of estrogen hormones.

Premarin is used after menopause to:

Premarin is also used to:

Who should not take Premarin?

Do not start taking Premarin if you:

Tell your healthcare provider:

How should I take Premarin?

What are the possible side effects of Premarin?

Less common but serious side effects include:

These are some of the warning signs of serious side effects:

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include:

Other side effects include:

These are not all the possible side effects of Premarin. For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of getting a serious side effect with Premarin?

General information about the safe and effective use of Premarin

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Premarin for conditions for which it was not prescribed. Do not give Premarin to other people, even if they have the same symptoms you have. It may harm them.

Keep Premarin out of the reach of children.

This leaflet provides a summary of the most important information about Premarin. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Premarin that is written for health professionals. You can get more information by calling the toll free number 800-934-5556.

What are the ingredients in Premarin?

Premarin contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates, 17 (alpha)-dihydroequilin, 17 (alpha)-estradiol, and 17 (beta)-dihydroequilin. Premarin 0.3 mg, 0.45 mg, 0.625 mg, and 0.9 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, microcrystalline cellulose, powdered cellulose, glyceryl monooleate, lactose monohydrate, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid (not present in 0.45 mg tablet), sucrose, and titanium dioxide.

Premarin 1.25 mg tablets contain the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose and titanium dioxide.

The tablets come in different strengths and each strength tablet is a different color. The color ingredients are:

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

This product's label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

Wyeth ®

Wyeth Pharmaceuticals Inc.  
Philadelphia, PA 19101
W10405C012
 
ET01
 
Rev 04/05


Copyright© 2006 Thomson PDR