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ENJUVIA® (synthetic conjugated estrogens, B) Tablets | ENJUVIA

04:55 EDT 27th August 2014 | BioPortfolio

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11001651

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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® (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 Δ-dehydroestrone sulfate.

The structural formulae for these estrogens are:

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.

IMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-01.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-02.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-03.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-04.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-05.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-06.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-07.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-08.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-09.jpgIMAGE b7aba0b2-72d1-4429-bb64-98b92e9d9433-10.jpg

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.

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)

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.

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.

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The mean (SD) apparent terminal elimination half-life (t) of conjugated estrone is 14 (± 6) hours and conjugated equilin is 11 (± 6) hours.

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

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.

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 ---

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 ---

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.

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 6: Relative And Absolute Risk Seen In The Estrogen-Alone Substudy Of WHINominal confidence intervals unadjusted for multiple looks and multiple comparisons 
Event Relative Risk
CE vs. Placebo

(95% nCI )
Placebo
n = 5,429
CE
n = 5,310
Absolute Risk per 10,000
Women-Years
CHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years
   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
StrokeResults are based on an average follow-up of 6.8 years  1.39 (1.10-1.77) 32 44
Deep vein thrombosis,Not included in Global Index 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, All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease 1.08 (0.88-1.32) 50 53
Overall mortality, 1.04 (0.88-1.32) 78 81
Global index, 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 1.01 (0.91-1.12) 190 192
Manufacturer

Duramed Pharmaceuticals Incorporated

Active Ingredients

Source

Drugs and Medications [1 Associated Drugs and Medications listed on BioPortfolio]

Enjuvia [Physicians Total Care, Inc.]

ENJUVIA® (synthetic conjugated estrogens, B) Tablets

Clinical Trials [0 Results]

None

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