Enjuvia

synthetic conjugated estrogens, b

Dosage Form: tablet
Enjuvia®

(synthetic conjugated estrogens, B) Tablets

11001651

Rx only

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 at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)

CARDIOVASCULAR AND OTHER RISKS

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.)

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

The estrogen-plus-progestin substudy of the WHI 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 5.6 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) per day, relative to placebo. (See CLINICAL STUDIES, and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer).

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with CE 0.625 mg alone and during 4 years of treatment with CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES, 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.

Enjuvia Description

Enjuvia® (synthetic conjugated estrogens, B) tablets contain a blend of ten (10) synthetic estrogenic substances. The estrogenic substances are: sodium estrone sulfate, sodium equilin sulfate, sodium 17α-dihydroequilin sulfate, sodium 17α-estradiol sulfate, sodium 17β-dihydroequilin sulfate, sodium 17α-dihydroequilenin sulfate, sodium 17β-dihydroequilenin sulfate, sodium equilenin sulfate, sodium 17β-estradiol sulfate, and sodium Δ8,9-dehydroestrone sulfate.

The structural formulae for these estrogens are:

Sodium Estrone Sulfate

Sodium Equilin Sulfate

Sodium 17α-Dihydroequilin Sulfate

Sodium 17α-Estradiol Sulfate

Sodium 17β-Dihydroequilenin Sulfate

Sodium 17α-Dihydroequilenin Sulfate

Sodium 17β-Estradiol Sulfate

Sodium Equilenin Sulfate

Sodium 17β-Dihydroequilenin Sulfate

Sodium Δ8,9 dehydroestrone Sulfate

Enjuvia 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, B. These tablets contain the following inactive ingredients: ascorbyl palmitate, butylated hydroxyanisole, colloidal silicon dioxide, edetate disodium dehydrate, plasticized ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, purified water, iron oxide red, titanium dioxide, polyethylene glycol, polysorbate 80, triacetate and triacetin/glycerol. In addition, the 0.45 mg tablets contain iron oxide black and iron oxide yellow; the 0.9 mg tablets also contain D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake and FD&C yellow no. 6 aluminum lake; and the 1.25 mg tablets contain iron oxide yellow.

Enjuvia - 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 in postmenopausal women.

A. Absorption

Synthetic conjugated estrogens, B are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. Enjuvia tablets release synthetic conjugated estrogens, B slowly over a period of several hours. Table 1 and Table 2 summarize the mean pharmacokinetic parameters for unconjugated (free) and conjugated (total) estrogens following single administration of two 0.625 mg tablets to 21 healthy postmenopausal women under fasting conditions. The effect of food on the bioavailability of synthetic conjugated estrogens, B following administration of Enjuvia tablets has not been studied. However, the presence of food did not significantly affect the pharmacokinetics of a similar formulation of synthetic conjugated estrogens, B.

Table 1. Mean Pharmacokinetic Parameters of Unconjugated (Free) Estrogens Following a Single Dose of 2 x 0.625 mg Enjuvia Tablets Under Fasting Conditions*

Cmax = peak plasma concentration; tmax = time peak concentration occurs; t1/2 = apparent terminal-phase disposition half-life. AUC0-48h = total area under the concentration-time curve from time zero to time of last quantifiable concentration (48h) ; * Δ8,9 Dehydroestrone (free) levels were below the assay limit of quantitation; CV= Coefficient of Variance
	Cmax (pg/mL)	tmax (hr)	t1/2 (hr)	AUC0-48h (pg●hr/mL)
Baseline-corrected estrone (% CV)	75.87 (39)	9.29 (25)	23.46 (59)	1601.59 (41)
Equilin (% CV)	41.94 (49)	8.38 (27)	15.09 (55)	707.21 (46)

Table 2. Mean Pharmacokinetic Parameters of Conjugated (Total) Estrogens Following a Single Dose of 2 x 0.625 mg Enjuvia Tablets Under Fasting Conditions

Cmax = peak plasma concentration; tmax = time peak concentration occurs; t1/2 = apparent terminal-phase disposition half-life; AUC0-48h = total area under the concentration-time curve from time zero to time of last quantifiable concentration (48h); CV= Coefficient of Variance
	Cmax (ng/mL)	tmax (h)	t1/2 (h)	AUC0-48h (ng●h/mL)
Baseline-corrected estrone (% CV)	3.74 (29)	8.00 (27)	14.26 (26)	62.03 (34)
Equilin (% CV)	3.69 (44)	8.05 (36)	11.28 (28)	58.25 (53)
Δ8,9 Dehydroestrone (%CV)	0.74 (32)	7.55 (37)	14.14 (26)	12.93 (39)

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 concentrations 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 portion 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. The mean (SD) apparent terminal elimination half-life (t½) of conjugated estrone is 14 (± 6) hours and conjugated equilin is 11 (± 6) hours.

E. Special Populations

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

F. Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s Wort 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, double-blind, placebo-controlled, dose-ranging, multi-center clinical study was conducted to evaluate the safety and effectiveness of Enjuvia tablets for the treatment of vasomotor symptoms in 281 naturally or surgically postmenopausal women aged 26 to 65 years who were experiencing a minimum of seven moderate to severe hot flushes per day or 50 per week at randomization. The majority (81%) of patients were Caucasian (n=228) and 17.4% were Black (n=49). Patients were randomized to receive Enjuvia tablets 0.3 mg, 0.625 mg, 1.25 mg, or placebo once daily for 12 weeks.

Enjuvia (0.3 mg, 0.625 mg and 1.25 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 3 and 4).

Table 3. Mean Number and Mean Change in Number of Moderate to Severe Hot Flushes Per Week ITT Population With LOCF

ITT= Intent to treat; LOCF= Last Observation Carried Forward, SD= Standard Deviation; SE= Standard Error
	0.3 mg n=66	0.625 mg n=71	1.25 mg n=69	Placebo n=70
Baseline
Mean (SD)	104.3 (57.7)	97.3 (82.1)	86.8 (42.1)	96.4 (58.2)
Week 4
Mean (SD)	47.0 (52.9)	23.3 (26.9)	24.6 (47.0)	57.8 (47.5)
Mean Change from    Baseline (SE)	-49.8 (5.2)	-72.8 (5.0)	-68.3 (5.1)	-37.2 (5.0)
p-value versus placebo	0.005	<0.001	<0.001	---
Week 12
Mean (SD)	30.7 (47.7)	12.2 (18.7)	12.4 (26.3)	47.5 (49.8)
Mean Change from    Baseline (SE)	-66.3 (4.6)	-84.6 (4.4)	-82.6 (4.5)	-48.3 (4.5)
p-value versus placebo	<0.001	<0.001	<0.001	---

Table 4. Mean Change in Severity of Moderate to Severe Hot Flushes Per Week, ITT Population with LOCF

ITT= Intent to treat; LOCF= Last Observation Carried Forward, SD= Standard Deviation; SE= Standard Error
	0.3 mg n=66	0.625 mg n=71	1.25 mg n=69	Placebo n=70
Baseline
Mean (SD)	2.5 (0.3)	2.5 (0.3)	2.5 (0.3)	2.5 (0.3)
Week 4
Mean (SD)	2.1 (0.8)	1.9 (1.0)	1.5 (1.1)	2.2 (0.8)
Mean Change from    Baseline (SE)	-0.5 (0.1)	-0.6 (0.1)	-1.0 (0.1)	-0.3 (0.1)
p-value versus placebo	0.036	0.002	<0.001	---
Week 12
Mean (SD)	1.5 (1.2)	1.1 (1.2)	1.0 (1.1)	1.9 (1.1)
Mean Change from    Baseline (SE)	-1.0 (0.1)	-1.4 (0.1)	-1.5 (0.1)	-0.6 (0.1)
p-value versus placebo	0.023	<0.001	<0.001	---

Effects on Vulvar and Vaginal Atrophy

A randomized, double-blind, placebo-controlled, multi-center clinical study was conducted to evaluate the safety and effectiveness of Enjuvia 0.3 mg tablets for the treatment of symptoms of vulvar and vaginal atrophy in 248 naturally or surgically postmenopausal women between 32 to 81 years of age (mean 58.6 years) who at baseline had ≤ 5% superficial cells on a vaginal smear, a vaginal pH > 5.0, and who identified their most bothersome moderate to severe symptom of vulvar and vaginal atrophy. The majority (82%) of the women were Caucasian (n=203), 11% were Hispanic (n=26), 4% were Black (n=9) and 3% were Asian (n=6). All patients were assessed for improvement in the mean change from baseline to Week 12 for three co-primary efficacy variables: most bothersome symptom of vulvar and vaginal atrophy (defined as the moderate to severe symptom that had been identified by the patient as most bothersome to her at baseline); percentage of vaginal superficial cells and percentage of vaginal parabasal cells; and vaginal pH.

In this study, a statistically significant mean change between baseline and week 12 for the group treated with Enjuvia 0.3 mg tablets compared to placebo was observed for the symptoms, vaginal dryness and pain with intercourse. See Table 5. Enjuvia 0.3 mg tablets increased superficial cells by a mean of 17.1% as compared to 2.0% for placebo (statistically significant). A corresponding statistically significant mean reduction from baseline in parabasal cells (41.7% for Enjuvia 0.3 mg tablets and 6.8% for placebo) was observed at week 12. The mean reduction between baseline and week 12 in the pH was 1.69 in the Enjuvia 0.3 mg tablets group and 0.45 in the placebo group (statistically significant).

Table 5. Change from Baseline to Week 12 in the Severity of Vaginal Dryness and Pain with Intercourse, Symptoms That Were Identified by the Menopausal Study Patient as Her Most Bothersome Symptom of Vulvar and Vaginal Atrophy at Baseline

* Treatment differences assessed by ANCOVA or rank ANCOVA (% cell data) with baseline as covariate for the modified intent-to-treat population, last-observation-carried-forward data set.
Most Bothersome Symptom at Baseline*	Enjuvia 0.3 mg	Placebo
Vaginal Dryness
n	56	54
Baseline Severity	2.52	2.54
Mean Severity at Week 12	0.80	1.81
Mean Change in Severity from Baseline (s.d.)	-1.71 (0.85)	-0.72 (0.66)
p-value vs. placebo	<0.001	---
Pain With Intercourse
n	35	40
Baseline Severity	2.74	2.70
Mean Severity at Week 12	0.94	1.95
Mean Change in Severity from Baseline (s.d.)	-1.80 (1.02)	-0.75 (0.95)
p-value vs. placebo	<0.001	---

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg) alone per day or in combination with medroxyprogesterone acetate (CE 0.625 mg/MPA 2.5 mg) 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 (MI), silent MI 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 (only in the estrogen plus progestin 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% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average follow-up of 6.8 years are presented in Table 6.

Table 6: Relative And Absolute Risk Seen In The Estrogen-Alone Substudy Of WHI* 

* Nominal confidence intervals unadjusted for multiple looks and multiple comparisons † Results are based on centrally adjudicated data for an average follow-up of 7.1 years ‡ Results are based on an average follow-up of 6.8 years § Not included in Global Index ¶ All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease # A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes
Event	Relative Risk CE vs. Placebo (95% nCI* )	Placebo n = 5,429	CE n = 5,310
		Absolute Risk per 10,000 Women-Years
CHD events†    Nonfatal MI†    CHD death†	0.95 (0.79- 1.16) 0.91 (0.73-1.14) 1.01(0.71- 1.43)	56 43 16	53 40 16
Stroke‡	1.39 (1.10-1.77)	32	44
Deep vein thrombosis†,§	1.47 (1.06-2.06)	15	23
Pulmonary embolism†	1.37 (0.90-2.07)	10	14
Invasive breast cancer†	0.80 (0.62-1.04)	34	28
Colorectal cancer‡	1.08 (0.75-1.55)	16	17
Hip fracture‡	0.61 (0.41-0.91)	17	11
Vertebral fractures‡, §	0.62 (0.42-0.93)	17	11
Total fractures‡, §	0.70 (0.63-0.79)	195	139
Death due to other causes‡, ¶	1.08 (0.88-1.32)	50	53
Overall mortality‡, §	1.04 (0.88-1.32)	78	81
Global index‡, #	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 estrogen-alone was 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 6).

The estrogen-plus-progestin substudy was also stopped early because, 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 (RR 1.15, 95% 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% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 7 below.

Table 7. Relative And Absolute Risk Seen in the Estrogen-Plus Progestin Substudy of WHI at an Average of 5.6 Years* 

* Results 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% nCI 0.82-1.18) † Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ‡ Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer
Event	Relative Risk CE/MPA vs. Placebo (95% nCI† )	Placebo n = 8102	CE/MPA n = 8506
		Absolute Risk per 10,000 Women-Years
CHD events    Non-fatal MI    CHD death	1.24 (1.00-1.54) 1.28 (1.00-1.63) 1.10 (0.70-1.75)	33 25 8	39 31 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 cancer‡	1.24 (1.01-1.54)	3	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 study, 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 conjugated estrogens (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% 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% were aged 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE 0.625 mg plus MPA 2.5 mg 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% CI 1.21-3.48) 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 WARNING, 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% CI 1.19-2.60). It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)

Indications and Usage for Enjuvia

Enjuvia tablets are indicated in the:

1. Treatment of moderate to severe vasomotor symptoms associated with menopause.


2. Treatment of moderate to severe vaginal dryness and pain with intercourse, symptoms of vulvar and vaginal atrophy, associated with menopause. When prescribing solely for the treatment of moderate to severe vaginal dryness and pain with intercourse, topical vaginal products should be considered.

Contraindications

Enjuvia tablets should not be used in women with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.


2. Known, suspected, or history of cancer of the breast.


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 the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).


6. Liver dysfunction or disease.


7. Known hypersensitivity to the ingredients of Enjuvia Tablets.


8. Known or suspected pregnancy. There is no indication for Enjuvia in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)

Warnings

See BOXED WARNINGS.

1. Cardiovascular disorders

Estrogen and estrogen/progestin therapies have been asso

Eplerenone

FULL PRESCRIBING INFORMATION

Indications and Usage for Eplerenone

Patient Selection Considerations

Serum potassium levels should be measured before initiating Eplerenone therapy and Eplerenone should not be prescribed if serum potassium is >5.5 mEq/L. [See 4 CONTRAINDICATIONS].

Congestive Heart Failure Post-Myocardial Infarction

Eplerenone is indicated to improve survival of stable patients with left ventricular (LV) systolic dysfunction (ejection fraction ≤40%) and clinical evidence of congestive heart failure (CHF) after an acute myocardial infarction (MI).

Hypertension

Eplerenone is indicated for the treatment of hypertension. Eplerenone may be used alone or in combination with other antihypertensive agents.

Eplerenone Dosage and Administration

Congestive Heart Failure Post-Myocardial Infarction

Treatment should be initiated at 25 mg once daily and titrated to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient. Eplerenone may be administered with or without food.

Once treatment with Eplerenone has begun, adjust the dose based on the serum potassium level as shown in Table 1.

Table 1: Dose Adjustment in Congestive Heart Failure Post-MI

Serum Potassium (mEq/L)	Action	Dose Adjustment
<5.0	Increase	25 mg every other day to 25 mg once daily 25 mg once daily to 50 mg once daily
5.0–5.4	Maintain	No adjustment
5.5–5.9	Decrease	50 mg once daily to 25 mg once daily 25 mg once daily to 25 mg every other day 25 mg every other day to withhold
≥ 6.0	Withhold	Restart at 25 mg every other day when potassium levels fall to <5.5 mEq/L

Hypertension

The recommended starting dose of Eplerenone is 50 mg administered once daily. The full therapeutic effect of Eplerenone is apparent within 4 weeks. For patients with an inadequate blood pressure response to 50 mg once daily the dosage of Eplerenone should be increased to 50 mg twice daily. Higher dosages of Eplerenone are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia. [See CLINICAL STUDIES, 14.2 Hypertension .]

Recommended Monitoring

Serum potassium should be measured before initiating Eplerenone therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter. Patient characteristics and serum potassium levels may indicate that additional monitoring is appropriate. [See WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia , ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings .] In the EPHESUS study [See CLINICAL STUDIES, 14.1 Congestive Heart Failure Post-Myocardial Infarction ], the majority of hyperkalemia was observed within the first three months after randomization.

In all patients taking Eplerenone who start taking a moderate CYP3A4 inhibitor, check serum potassium and serum creatinine in 3 to 7 days. 

Dose Modifications for Specific Populations

For hypertensive patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin, saquinavir, verapamil and fluconazole), the starting dose of Eplerenone should be reduced to 25 mg once daily. [See DRUG INTERACTIONS, 7.1 CYP3A4 Inhibitors.]

No adjustment of the starting dose is recommended for the elderly or for patients with mild-to-moderate hepatic impairment. [See CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics.]

Dosage Forms and Strengths

• 25 mg tablets: round, white, film-coated tablets debossed with "SZ" on one side and "12" on the other.


• 50 mg tablets: round, yellow film-coated tablets debossed with "SZ" on one side and "16" on the other.

Contraindications

For All Patients

Eplerenone tablets are contraindicated in all patients with:

• serum potassium >5.5 mEq/L at initiation,


• creatinine clearance ≤30 mL/min, or


• concomitant administration of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir). [See DRUG INTERACTIONS, 7.1 CYP3A4 Inhibitors, CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics.]

 For Patients Treated for Hypertension

Eplerenone tablets is contraindicated for the treatment of hypertension in patients with:

• type 2 diabetes with microalbuminuria,


• serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females,


• creatinine clearance <50 mL/min, or


• concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone or triamterene). [See WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia , ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings , 7 DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics.]

Warnings and Precautions

Hyperkalemia

Minimize the risk of hyperkalemia with proper patient selection and monitoring and avoidance of certain concomitant medications [See 4 CONTRAINDICATIONS, ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings ) and 7 DRUG INTERACTIONS]. Monitor patients for the development of hyperkalemia until the effect of Eplerenone is established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue Eplerenone therapy with proper dose adjustment. Dose reduction decreases potassium levels. [See DOSAGE AND ADMINISTRATION, 2.1 Congestive Heart Failure Post-Myocardial Infarction .]

The rates of hyperkalemia increase with declining renal function. [See ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings .] Patients with hypertension who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50mL/min should not be treated with Eplerenone [See 4 CONTRAINDICATIONS]. Patients with CHF post-MI who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50mL/min should be treated with Eplerenone with caution.

Diabetic patients with CHF post-MI should also be treated with caution, especially those with proteinuria. The subset of patients in the EPHESUS study with both diabetes and proteinuria on the baseline urinalysis had increased rates of hyperkalemia compared to patients with either diabetes or proteinuria. [See ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings .]

Impaired Hepatic Function

Mild-to-moderate hepatic impairment did not increase the incidence of hyperkalemia. In 16 subjects with mild-to-moderate hepatic impairment who received 400 mg of Eplerenone, no elevations of serum potassium above 5.5 mEq/L were observed. The mean increase in serum potassium was 0.12 mEq/L in patients with hepatic impairment and 0.13 mEq/L in normal controls. The use of Eplerenone in patients with severe hepatic impairment has not been evaluated. [See CLINICAL PHARMACOLOGY, 12 CLINICAL PHARMACOLOGY.]

Impaired Renal Function

Patients with decreased renal function are at increased risk of hyperkalemia. [See 4 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia , ADVERSE REACTIONS, 6.1 Clinical Trials Experience .]

Allergic Reaction

Eplerenone Tablets 50 mg contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hyperkalemia [See WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia ]

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 clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS, safety was evaluated in 3,307 patients treated with Eplerenone and 3,301 placebo-treated patients. The overall incidence of adverse events reported with Eplerenone (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% Eplerenone vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, myocardial infarction and abnormal renal function.

Adverse reactions that occurred more frequently in patients treated with Eplerenone than placebo were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%). Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups. Hypokalemia occurred less frequently in patients treated with Eplerenone (0.6% vs. 1.6%).

The rates of sex hormone-related adverse events are shown in Table 2.

Table 2: Rates of Sex Hormone-Related Adverse Events in EPHESUS

	Rates in Males			Rates in Females
	Gynecomastia	Mastodynia	Either	Abnormal Vaginal Bleeding
Eplerenone	0.4 %	0.1%	0.5%	0.4%
Placebo	0.5 %	0.1%	0.6%	0.4%

Hypertension

Eplerenone has been evaluated for safety in 3,091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year.

In placebo-controlled studies, the overall rates of adverse events were 47% with Eplerenone and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender or race. Therapy was discontinued due to an adverse event in 3% of patients treated with Eplerenone and 3% of patients given placebo. The most common reasons for discontinuation of Eplerenone were headache, dizziness, angina pectoris/myocardial infarction and increased GGT. The adverse events that were reported at a rate of at least 1% of patients and at a higher rate in patients treated with Eplerenone in daily doses of 25 mg to 400 mg versus placebo are shown in Table 3.

Table 3: Rates (%) of Adverse Events Occurring in Placebo-Controlled Hypertension Studies in ≥1% of Patients Treated with Eplerenone (25 mg to 400 mg) and at a More Frequent Rate than in Placebo-Treated Patients

	Eplerenone (n=945)	Placebo (n=372)
Metabolic Hypercholesterolemia Hypertriglyceridemia	1 1	0 0
Digestive Diarrhea Abdominal pain	2 1	1 0
Urinary Albuminuria	1	0
Respiratory Coughing	2	1
Central/Peripheral Nervous System Dizziness	3	2
Body as a Whole
Fatigue Influenza-like symptoms	2 2	1 1

Note: Adverse events that are too general to be informative or are very common in the treated population are excluded.

Gynecomastia and abnormal vaginal bleeding were reported with Eplerenone but not with placebo. The rates of these sex hormone-related adverse events are shown in Table 4. The rates increased slightly with increasing duration of therapy. In females, abnormal vaginal bleeding was also reported in 0.8% of patients on antihypertensive medications (other than spironolactone) in active control arms of the studies with Eplerenone.

Table 4: Rates of Sex Hormone-Related Adverse Events with Eplerenone in Hypertension Clinical Studies

	Rates in Males			Rates in Females
	Gynecomastia	Mastodynia	Either	Abnormal Vaginal Bleeding
All controlled studies	0.5%	0.8%	1.0%	0.6%
Controlled studies lasting ≥ 6 months	0.7%	1.3%	1.6%	0.8%
Open label, long-term study	1.0%	0.3 %	1.0 %	2.1 %

Clinical Laboratory Test Findings

Congestive Heart Failure Post-Myocardial Infarction

Creatinine: Increases of more than 0.5 mg/dL were reported for 6.5% of patients administered Eplerenone and for 4.9% of placebo-treated patients.

Potassium: In EPHESUS [see CLINICAL STUDIES, 14.1 Congestive Heart Failure Post-Myocardial Infarction ], the frequency of patients with changes in potassium (<3.5 mEq/L or >5.5 mEq/L or ≥6.0 mEq/L) receiving Eplerenone compared with placebo are displayed in Table 5.

Table 5: Hypokalemia (<3.5 mEq/L) or Hyperkalemia (>5.5 or ≥6.0 mEq/L) in EPHESUS

Potassium (mEq/L)	Eplerenone (N=3,251) n (%)	Placebo (N=3,237) n (%)
<3.5	273 (8.4)	424 (13.1)
>5.5	508 (15.6)	363 (11.2)
≥ 6.0	180 (5.5)	126 (3.9)

Table 6 shows the rates of hyperkalemia in EPHESUS as assessed by baseline renal function (creatinine clearance).

Table 6: Rates of Hyperkalemia (>5.5 mEq/L)in EPHESUS by Baseline Creatinine Clearance*

* Estimated using the Cockroft-Gault formula.
Baseline Creatinine Clearance	Eplerenone (N=508) n (%)	Placebo (N=363) n (%)
≤30 mL/min	160 (32)	82 (23)
31–50 mL/min	122 (24)	46 (13)
51–70 mL/min	86 (17)	48 (13)
>70 mL/min	56 (11)	32 (9)

Table 7 shows the rates of hyperkalemia in EPHESUS as assessed by two baseline characteristics: presence/absence of proteinuria from baseline urinalysis and presence/absence of diabetes. [See WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia .]

Table 7: Rates of Hyperkalemia ( >5.5 mEq/L)in EPHESUS by Proteinuria and History of Diabetes*

* Diabetes assessed as positive medical history at baseline; proteinuria assessed by positive dipstick urinalysis at baseline.
	Eplerenone (N=508) n (%)	Placebo (N=363) n (%)
Proteinuria, no Diabetes	81 (16)	40 (11)
Diabetes, no Proteinuria	91 (18)	47 (13)
Proteinuria and Diabetes	132 (26)	58 (16)

Hypertension

Potassium: In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 8 along with the frequencies of values >5.5 mEq/L.

Table 8: Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of Eplerenone

		Mean Increase mEq/L	%> 5.5 mEq/L
Daily Dosage	n
Placebo	194	0	1
25	97	0.08	0
50	245	0.14	0
100	193	0.09	1
200	139	0.19	1
400	104	0.36	8.7

Patients with both type 2 diabetes and microalbuminuria are at increased risk of developing persistent hyperkalemia. In a study of such patients taking Eplerenone 200 mg, the frequencies of maximum serum potassium levels >5.5 mEq/L were 33% with Eplerenone given alone and 38% when Eplerenone was given with enalapril.

Rates of hyperkalemia increased with decreasing renal function. In all studies, serum potassium elevations >5.5 mEq/L were observed in 10.4% of patients treated with Eplerenone with baseline calculated creatinine clearance <70 mL/min, 5.6% of patients with baseline creatinine clearance of 70 mL/min to 100 mL/min and 2.6% of patients with baseline creatinine clearance of >100 mL/min. [See WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia .]

Sodium: Serum sodium decreased in a dose-related manner. Mean decreases ranged from 0.7 mEq/L at 50 mg daily to 1.7 mEq/L at 400 mg daily. Decreases in sodium (<135 mEq/L) were reported for 2.3% of patients administered Eplerenone and 0.6% of placebo-treated patients.

Triglycerides: Serum triglycerides increased in a dose-related manner. Mean increases ranged from 7.1 mg/dL at 50 mg daily to 26.6 mg/dL at 400 mg daily. Increases in triglycerides (above 252 mg/dL) were reported for 15% of patients administered Eplerenone and 12% of placebo-treated patients.

Cholesterol: Serum cholesterol increased in a dose-related manner. Mean changes ranged from a decrease of 0.4 mg/dL at 50 mg daily to an increase of 11.6 mg/dL at 400 mg daily. Increases in serum cholesterol values greater than 200 mg/dL were reported for 0.3% of patients administered Eplerenone and 0% of placebo-treated patients.

Liver Function Tests: Serum alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT) increased in a dose-related manner. Mean increases ranged from 0.8 U/L at 50 mg daily to 4.8 U/L at 400 mg daily for ALT and 3.1 U/L at 50 mg daily to 11.3 U/L at 400 mg daily for GGT. Increases in ALT levels greater than 120 U/L (3 times upper limit of normal) were reported for 15/2,259 patients administered Eplerenone and 1/351 placebo-treated patients. Increases in ALT levels greater than 200 U/L (5 times upper limit of normal) were reported for 5/2,259 of patients administered Eplerenone and 1/351 placebo-treated patients. Increases of ALT greater than 120 U/L and bilirubin greater than 1.2 mg/dL were reported 1/2,259 patients administered Eplerenone and 0/351 placebo-treated patients. Hepatic failure was not reported in patients receiving Eplerenone.

BUN/Creatinine: Serum creatinine increased in a dose-related manner. Mean increases ranged from 0.01 mg/dL at 50 mg daily to 0.03 mg/dL at 400 mg daily. Increases in blood urea nitrogen to greater than 30 mg/dL and serum creatinine to greater than 2 mg/dL were reported for 0.5% and 0.2%, respectively, of patients administered Eplerenone and 0% of placebo-treated patients.

Uric Acid: Increases in uric acid to greater than 9 mg/dL were reported in 0.3% of patients administered Eplerenone and 0% of placebo-treated patients.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Eplerenone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin: angioneurotic edema, rash

Drug Interactions

CYP3A4 Inhibitors

Because Eplerenone metabolism is predominantly mediated via CYP3A4, do not use Eplerenone with drugs that are strong inhibitors of CYP3A4. [See 4 CONTRAINDICATIONS and CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics.]

In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of Eplerenone to 25 mg once daily. [See DOSAGE AND ADMINISTRATION, 2.4 Dose Modifications for Specific Populations ) and CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics.]

ACE Inhibitors and Angiotensin II Receptor Antagonists

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS [see CLINICAL STUDIES, 14.1 Congestive Heart Failure Post-Myocardial Infarction ], 3,020 (91%) patients receiving Eplerenone 25 mg to 50 mg also received ACE inhibitors or angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels >5.5 mEq/L were similar regardless of the use of ACEI/ARB.

Hypertension

In clinical studies of patients with hypertension, the addition of Eplerenone 50 mg to 100 mg to ACE inhibitors and angiotensin II receptor antagonists increased mean serum potassium slightly (about 0.09 mEq/L to 0.13 mEq/L). In a study in diabetics with microalbuminuria, Eplerenone 200 mg combined with the ACE inhibitor enalapril 10 mg increased the frequency of hyperkalemia (serum potassium >5.5 mEq/L) from 17% on enalapril alone to 38%.

Lithium

A drug interaction study of Eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if Eplerenone is administered concomitantly with lithium.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A drug interaction study of Eplerenone with an NSAID has not been conducted. The administration of other potassium-sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Therefore, when Eplerenone and NSAIDs are used concomitantly, patients should be observed to determine whether the desired effect on blood pressure is obtained and monitored for changes in serum potassium levels.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Eplerenone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects

Embryo-fetal development studies were conducted with doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to 32 and 31 times the human AUC for the 100-mg/day therapeutic dose, respectively). No teratogenic effects were seen in rats or rabbits, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage. Because animal reproduction studies are not always predictive of human response, Eplerenone should be used during pregnancy only if clearly needed.

Nursing Mothers

The concentration of Eplerenone in human breast milk after oral administration is unknown. However, preclinical data show that Eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk:plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing. Rat pups exposed by this route developed normally. Because many drugs are excreted in human milk and because of the unknown potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

In a 10-week study of 304 hypertensive pediatric patients age 4 to 17 years treated with Eplerenone up to 100 mg per day, doses that produced exposure similar to that in adults, Eplerenone did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients, the incidence of reported adverse events was similar to that of adults.

Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness.

Eplerenone has not been studied in pediatric patients with heart failure.

Geriatric Use

Congestive Heart Failure Post-Myocardial Infarction

Of the total number of patients in EPHESUS, 3,340 (50%) were 65 and over, while 1,326 (20%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of Eplerenone. [See CLINICAL STUDIES, 14.1 Congestive Heart Failure Post-Myocardial Infarction .]

No differences in overall incidence of adverse events were observed between elderly and younger patients. However, due to age-related decreases in creatinine clearance, the incidence of laboratory-documented hyperkalemia was increased in patients 65 and older. [See WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia .]

Hypertension

Of the total number of subjects in clinical hypertension studies of Eplerenone, 1,123 (23%) were 65 and over, while 212 (4%) were 75 and over. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects.

Overdosage

No cases of human overdosage with Eplerenone have been reported. Lethality was not observed in mice, rats or dogs after single oral doses that provided Cmax exposures at least 25 times higher than in humans receiving Eplerenone 100 mg/day. Dogs showed emesis, salivation and tremors at a Cmax 41 times the human therapeutic Cmax, progressing to sedation and convulsions at higher exposures. The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalemia. Eplerenone cannot be removed by hemodialysis. Eplerenone has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be instituted. If hyperkalemia develops, standard treatment should be initiated.

Eplerenone Description

Eplerenone tablets contains Eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor.

Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C24H30O6 and it has a molecular weight of 414.50.

The structural formula of Eplerenone is represented below:

Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH independent. The octanol/water partition coefficient of Eplerenone is approximately 7.1 at pH 7.0.

Eplerenone tablets for oral administration contains 25 mg or 50 mg of Eplerenone and the following inactive ingredients: lactose monohydrate, silicified microcrystalline cellulose, croscarmellose sodium, hypromellose, talc, magnesium stearate, titanium dioxide, polyethylene glycol. In addition, the 25 mg tablets also contain polysorbate and the 50 mg tablets also contain FD&C yellow No. 5 (tartrazine) and FD&C yellow No. 6, polydextrose and triacetin.

Eplerenone - Clinical Pharmacology

Mechanism of Action

Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.

Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of Eplerenone.

Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.

Pharmacokinetics

Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 4 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A4 (e.g., ketoconazole, saquinavir) increase blood levels of Eplerenone.

Absorption and Distribution

Mean peak plasma concentrations of Eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of Eplerenone is 69% following administration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 mg to 100 mg and less than proportional at doses above 100 mg.

The plasma protein binding of Eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 43 L to 90 L. Eplerenone does not preferentially bind to red blood cells.

Metabolism and Excretion

Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of Eplerenone have been identified in human plasma.

Less than 5% of an Eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of Eplerenone is approximately 4 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.

Age, Gender and Race

The pharmacokinetics of Eplerenone at a dose of 100 mg once daily has been investigated in the elderly (≥65 years), in males and females and in Blacks. At steady state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). The pharmacokinetics of Eplerenone did not differ significantly between males and females. At steady state, Cmax was 19% lower and AUC was 26% lower in Blacks. [See DOSAGE AND ADMINISTRATION,2.4 Dose Modifications for Specific Populations and USE IN SPECIFIC POPULATIONS, 8.5 Geriatric Use.]

Renal Impairment

The pharmacokinetics of Eplerenone was evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. Compared with control subjects, steady-state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of Eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis. [See WARNINGS AND PRECAUTIONS, 5.3 Impaired Renal Function .]

Hepatic Impairment

The pharmacokinetics of Eplerenone 400 mg has been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state Cmax and AUC of Eplerenone were increased by 3.6% and 42%, respectively.

Heart Failure

The pharmacokinetics of Eplerenone 50 mg was evaluated in 8 patients with heart failure (NYHA classification II–IV) and 8 matched (gender, age, weight) healthy controls. Compared with the controls, steady state AUC and Cmax in patients with stable heart failure were 38% and 30% higher, respectively.

Drug-Drug Interactions [See 7 DRUG INTERACTIONS.]

Eplerenone is metabolized primarily by CYP3A4. Inhibitors of CYP3A4 cause increased exposure [see DRUG INTERACTIONS, 7.1 CYP3A4 Inhibitors].

Drug-drug interaction studies were conducted with a 100 mg dose of Eplerenone.

A pharmacokinetic study evaluating the administration of a single dose of Eplerenone 100 mg with ketoconazole 200 mg two times a day, a strong inhibitor of the CYP3A4 pathway, showed a 1.7-fold increase in Cmax of Eplerenone and a 5.4-fold increase in AUC of Eplerenone.

Administration of Eplerenone with moderate CYP3A4 inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in Cmax of Eplerenone ranging from 1.4- to 1.6-fold and AUC from 2.0- to 2.9-fold.

Grapefruit juice caused only a small increase (about 25%) in exposure.

Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9 or CYP2D6. Eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide, triazolam, verapamil and warfarin in vitro. Eplerenone is not a substrate or an inhibitor of P-Glycoprotein at clinically relevant doses.

No clinically significant drug-drug pharmacokinetic interactions were observed when Eplerenone was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin or warfarin. St. John's Wort (a CYP3A4 inducer) caused a small (about 30%) decrease in Eplerenone AUC.

No significant changes in Eplerenone pharmacokinetics were observed when Eplerenone was administered with aluminum- and magnesium-containing antacids.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Eplerenone was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis (Ames test in Salmonella spp. and E. Coli), in vitro mammalian cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation and in vivo/ex vivo unscheduled DNA synthesis in rat liver.

There was no drug-related tumor response in heterozygous P53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered Eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of Eplerenone to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific mechanism have not shown a similar effect in humans.

Male rats treated with Eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility. Dogs administered Eplerenone at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline in libido, sexual performance or semen quality. Testicular weight and histology were not affected by Eplerenone in any test animal species at any dosage.

Clinical Studies

Congestive Heart Failure Post-Myocardial Infarction

The Eplerenone post-acute myocardial infarction heart f