irculating reservoir for the formation of more active estrogens. Although the clinical significance has not been determined, estradiol from EstroGel does not go through first-pass liver metabolism.
D. Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
The apparent terminal exponential half-life for estradiol was about 36 hours following administration of 1.25 g EstroGel.
E. Special populations
EstroGel has been studied only in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
F. Drug interactions
No formal drug interaction studies have been conducted for EstroGel.
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 estrogen and may result in side effects.
G. Potential for estradiol transfer and effects of washing
The effect of estradiol transfer was eva luated in 24 healthy postmenopausal women who topically applied 1.25 g of EstroGel once daily on the posterior surface of 1 arm from wrist to shoulder for a period of 14 consecutive days. On each day, 1 hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes. No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered EstroGel.
The effect of application site washing on the serum concentrations of estradiol was determined in 24 healthy postmenopausal females who applied 1.25 g of EstroGel once daily for 14 consecutive days. Site washing 1 hour after the application resulted in a 22% mean decrease in average 24-hour serum concentrations of estradiol.
CLINICAL STUDIES
Effects on vasomotor symptoms
In a placebo-controlled study, 145 postmenopausal women between 29 and 67 years of age (81.4% were White) were randomly assigned to receive 1.25 g of EstroGel (containing 0.75 mg of estradiol) or placebo gel for 12 weeks. Efficacy was assessed at 4 and 12 weeks of treatment. A statistically significant reduction in the frequency and severity of moderate to severe hot flushes was shown at Weeks 4 and 12. (See Table 1)
TABLE 1 Mean Change from Baseline in the Number and Severity of Hot Flushes per Day, ITT Population, LOCF *
Primary timepoint
P values from Elteren’s nonparametric test.
Statistically significantly different from placebo.
Number of Hot Flushes/Day
(Moderate to Severe) Severity Score/Day
(Mild, Moderate, Severe)
Placebo
n=73 EstroGel 1.25 g
n=72 Placebo
n=73 EstroGel 1.25 g
n=72
Baseline
Mean (SD) 11.01 (5.66) 10.33 (3.07) 2.30 (0.24) 2.36 (0.29)
Week 4*
Mean (SD)
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