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Synthetic Conjugated Estrogens (Synthetic Conjugated Estrogens) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Synthetic conjugated estrogens, A tablets contain a blend of nine (9) synthetic estrogenic substances. The estrogenic substances are sodium estrone sulfate, sodium equilin sulfate, sodium 17(alpha)-dihydroequilin sulfate, sodium 17(alpha)-estradiol sulfate, sodium 17(beta)-dihydroequilin sulfate, sodium 17(alpha)-dihydroequilenin sulfate, sodium 17(beta)-dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17(beta)-estradiol sulfate.

The structural formulae for these estrogens are:

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 synthetic conjugated estrogens, A. Tablets also contain the following inactive ingredients: ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, titanium dioxide, and triethyl citrate.

-0.3 mg tablets also contain FD&C Blue No. 2 aluminum lake and D&C Yellow No. 10 aluminum lake.

-0.45 mg tablets also contain FD&C Yellow No. 6/Sunset Yellow FCF lake.

-0.625 mg tablets also contain FD&C Red No. 40 aluminum lake.

-0.9 mg tablets do not contain additional color additives.

-1.25 mg tablets also contain FD&C Blue No. 2 aluminum lake.

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 hormones seen in postmenopausal women.

PHARMACOKINETICS

ABSORPTION

Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several hours. The effect of food on the bioavailability of synthetic conjugated estrogens, A from Cenestin has not been studied.

Table 1
PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS IN HEALTHY POSTMENOPAUSAL WOMEN UNDER FASTING CONDITIONS
Pharmacokinetic Parameters of Unconjugated Estrogens Following a Dose of 2 × 0.625 mg Cenestin
Drug Cmax
(pg/mL)
CV%
tmax
(h)
CV%
AUC0-72h
(pg·hr/mL)
CV%
Baseline-corrected estrone 84.5 (41.7) 8.25 (35.6) 1749 (43.8)
Equilin 45.6 (47.3) 7.78 (28.8)   723 (67.9)
Pharmacokinetic Parameters of Conjugated Estrogens Following a Dose of 2 × 0.625 mg Cenestin
Drug Cmax
(ng/mL)
CV%
tmax
(h)
CV%
t½
(h)
CV%
AUC0-72h
(ng·hr/mL)
CV%
Baseline-corrected estrone 4.43 (40.4) 7.7 (30.3) 10.6 (25.4) 69.89 (39.2)
Equilin 3.27 (43.5) 5.8 (31.1)   9.7 (23.0) 46.46 (47.5)

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 concentrations 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 portion of the circulating estrogens exist 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

Cenestin was investigated in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

DRUG INTERACTIONS

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers and 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

A randomized, placebo-controlled multicenter clinical study was conducted evaluating the effectiveness of Cenestin for the treatment of moderate to severe vasomotor symptoms in 120 postmenopausal women between 38 and 66 years of age (68% were Caucasian). Patients were randomized to receive either placebo or 0.625 mg Cenestin daily for 12 weeks. Dose titration was allowed after one week of treatment. The starting dose was either doubled (2 × 0.625 mg Cenestin or placebo taken daily) or reduced (0.3 mg Cenestin or placebo taken daily), if necessary. Efficacy was assessed at 4 and 12 weeks of treatment. By week 12, 10% of the study participants remained on a single 0.625 mg Cenestin tablet daily while 77% required two (0.625 mg) tablets daily. The results in Table 2 indicate that compared to placebo, Cenestin produced a reduction in moderate to severe vasomotor symptoms at weeks 4 and 12.

A second randomized, placebo-controlled multicenter clinical study was conducted evaluating the effectiveness of 0.45 mg Cenestin tablets, for the treatment of moderate to severe vasomotor symptoms in 104 menopausal women between 52 and 74 years of age (76% were Caucasian). Patients were randomized to receive either placebo or 0.45 mg Cenestin daily for 12 weeks. Efficacy was assessed at 4 and 12 weeks of treatment. The mean change in the number of moderate to severe hot flushes per week shown in Table 3 indicate that compared to placebo, 0.45 mg Cenestin produced a reduction in moderate to severe vasomotor symptoms at weeks 4 and 12. A corresponding reduction in the severity of hot flushes was demonstrated at weeks 5 and 12.

Table 2
Clinical Responsea
Mean Change in the Number of Moderate to Severe Hot
Flushes Per Week, 0.625 mg and 2 × 0.625 mg Cenestin, ITT Population
Cenestin b
0.625 mg and
2 × 0.625 mg (n=70)
Placebo (n=47)
Baseline
  Mean # (SD) 96.8 (42.6) 94.1 (33.9)
Week 4
  Mean # (SD) 28.7 (28.8) 45.7 (36.8)
  Mean Change from
  Baseline (SD)
-68.1 (43.9) -48.4 (46.2)  
  P-value vs. Placebo p=.022  
Week 12
  Mean # (SD) 16.5 (25.7) 37.8 (38.7)
  Mean Change from
  Baseline (SD)
-80.3 (50.3) -56.3 (48.0) 
  P-value vs. Placebo p=.010  
Mean = Arithmetic Mean, SD = Standard Deviation
a Intent-to-treat population = 117
b: Combined results for 0.625 mg and 0.625 mg Cenestin tablets.

Table 3
Clinical Response *
Mean Change in the Number of Moderate to Severe Hot Flushes Per Week, 0.45 mg Cenestin, ITT Population
Cenestin
0.45 mg (n=53)
Placebo (n=51)
Baseline
  Mean # (SD) 95.9 (37.0) 95.9 (41.6)
Week 4
  Mean # (SD) 45.7 (45.9) 59.4 (46.2)
  Mean Change from
  Baseline (SD)
-50.3 (35.4) -36.5 (42.9)
  P-value vs. Placebo p=.014  
Week 12
  Mean # (SD) 26.1 (43.0) 50.5 (48.4)
  Mean Change from
  Baseline (SD)
-69.9 (38.1) -45.4 (44.7)
  P-value vs. Placebo p<.001  
Mean = Arithmetic Mean, SD = Standard Deviation
*Intent-to-treat population = 104

EFFECTS ON VULVAR AND VAGINAL ATROPHY

The effects of 0.3 mg Cenestin on moderate to severe symptoms of vulvar and vaginal atrophy were confirmed in a 16-week, randomized, placebo-controlled, multicenter clinical study in 72 postmenopausal women between 30 and 77 years of age (53% were Caucasian). Patients were randomized to receive either placebo or 0.3 mg Cenestin daily for 16 weeks. Efficacy was assessed at weeks 12 and 16 for vaginal wall cytology and week 16 for vaginal pH. Results for percent of superficial cells from a maturation index of the vaginal mucosa are shown in Figure 2. Mean vaginal pH decreased from a baseline of 6.20 to 5.14 for Cenestin and increased to 6.15 from a baseline of 6.03 for placebo.

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 oral 0.625 mg conjugated equine estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in 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 CE or CE/MPA on menopausal symptoms.

The CE-only substudy is continuing and results have not been reported. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA 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 4 below:

Table 4
Relative and Absolute Risk Seen in the Estrogen/Progestin Substudy of the WHI a
Event c Relative Risk
Conjugated Equine Estrogens/Medroxyprogesterone Acetate vs Placebo at 5.2 years (95% CI *)
Placebo n = 8102 CEE/MPA n = 8506
Absolute Risk per 10,000 Person-years
CHD events 1.29 (1.02-1.63)   30   37
   Non-fatal MI 1.32 (1.02-1.72)   23   30
   CHD death 1.18 (0.70-1.97)    6    7
Invasive breast cancer b 1.26 (1.00-1.59)   30   38
Stroke 1.41 (1.07-1.85)   21   29
Pulmonary embolism 2.13 (1.39-3.25)    8   16
Colorectal cancer 0.63 (0.43-0.92)   16   10
Endometrial cancer 0.83 (0.47-1.47)    6    5
Hip fracture 0.66 (0.45-0.98)   15   10
Death due to causes other than the events above 0.92 (0.74-1.14)   40   37
Global index c 1.15 (1.03-1.28) 151 170
Deep vein thrombosis d 2.07 (1.49-2.87)   13   26
Vertebral fractures d 0.66 (0.44-0.98)   15    9
Other osteoporotic fractures d 0.77 (0.69-0.86) 170 131
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 "global index," absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while 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 BOX WARNINGS, WARNINGS, and PRECAUTIONS.)

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