ENJUVIA (Page 2 of 8)

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

-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

-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

-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

-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

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.