Premarin (Conjugated Estrogens) - Clinical Pharmacology

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

A. Absorption

Conjugated estrogens are water-soluble 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 1 x 0.625 mg and 1 x 1.25 mg tablets to healthy postmenopausal women.

The pharmacokinetics of Premarin 0.45 mg and 1.25 mg tablets were assessed following a single dose with a high-fat breakfast and with fasting administration. The C_max and AUC of estrogens were altered approximately 3-13%. The changes to C_max and AUC are not considered clinically meaningful.

TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN

Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter Arithmetic Mean (%CV)	Cmax (pg/mL)	tmax (h)	t1/2 (h)	AUC (pg•h/mL)
Estrone	87 (33)	9.6 (33)	50.7 (35)	5557 (59)
Baseline-adjusted estrone	64 (42)	9.6 (33)	20.2 (40)	1723 (52)
Equilin	31 (38)	7.9 (32)	12.9 (112)	602 (54)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter Arithmetic Mean (%CV)	Cmax (ng/mL)	tmax (h)	t1/2 (h)	AUC (ng•h/mL)
Total Estrone	2.7 (43)	6.9 (25)	26.7 (33)	75 (52)
Baseline-adjusted total estrone	2.5 (45)	6.9 (25)	14.8 (35)	46 (48)
Total Equilin	1.8 (56)	5.6 (45)	11.4 (31)	27 (56)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter Arithmetic Mean (%CV)	Cmax (pg/mL)	tmax (h)	t1/2 (h)	AUC (pg•h/mL)
Estrone	124 (30)	10.0 (32)	38.1 (37)	6332 (44)
Baseline-adjusted estrone	102 (35)	10.0 (32)	19.7 (48)	3159 (53)
Equilin	59 (43)	8.8 (36)	10.9 (47)	1182 (42)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter Arithmetic Mean (%CV)	Cmax (ng/mL)	tmax (h)	t1/2 (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)

B. 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.

C. 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 intestine 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.

D. Excretion

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

E. Special Populations

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

F. 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 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 ------------------
Time Period (week)	Baseline Mean ± SD	Observed Mean ± SD	Mean Change ± SD	p-Values vs. Placeboa
a: Based on analysis of covariance with treatment as factor and baseline as covariate.
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) PERCENTCHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS AND PLACEBO

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

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled 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 YEARS^a

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.)