Label: DIVIGEL- estradiol gel

A.      Absorption

Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor.

In a 14-day, Phase 1, multiple-dose study, Divigel® demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC0-24 and Cmax following once daily dosing to the skin of either the right or left upper thigh (Table 1).

Steady-state serum concentration of estradiol are achieved by day 12 following daily application of Divigel® to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1.

Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of Divigel 0.1%

The effect of sunscreens and other topical lotions on the systemic exposure of Divigel® has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels.

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

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 proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Estradiol from Divigel® avoids first pass metabolism and provides estradiol/estrone ratios at steady state in the range of 0.42 to 0.65.

D.      Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of Divigel®.

E.      Special Populations

Divigel® 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

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 result in side effects.

G.      Potential for Estradiol Transfer and Effects of Washing

As with most topical products, there is a potential for estradiol transfer following physical contact with Divigel® application sites. The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 g of Divigel® (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh- to- arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive.

The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 g of Divigel® to a 200 cm2 area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin, and resulted in a 30-38% decrease in the mean total 24-hour exposure to estradiol.

Effects on Vasomotor Symptoms

A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of Divigel® for vasomotor symptoms in 495 postmenopausal women (86.5% White; 10.1% Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2 week period prior to treatment). Subjects applied placebo, Divigel® 0.25 g (0.25 mg estradiol), Divigel® 0.5 g (0.5 mg estradiol) or Divigel® 1.0 g (1.0 mg estradiol) once daily to the thigh. Reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes were statistically significant for the 0.5 g/day and the 1.0 g/day Divigel® doses when compared to placebo at week 4. Statistically significant reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes for the Divigel® 0.25 g/day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in median daily frequency and severity of hot flushes for all three Divigel® doses (0.25 g/day, 0.5 g/day and 1.0 g/day) compared to placebo at week 12. See Table 2 for results.

a.      Stroke

In the estrogen-alone substudy of the Women's Health Initiative (WHI), a statistically significant increased risk of stroke was observed in women receiving CE 0.625 mg daily compared to placebo (44 versus 32 per 10,000 women-years). The increase in risk was observed in year 1 and persisted. (See CLINICAL STUDIES.)

In the estrogen-plus-progestin substudy of the WHI study, a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to women receiving placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted.

b.      Coronary heart disease

In the estrogen-alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or death, due to CHD) was reported in women receiving estrogen-alone compared to placebo. (See CLINICAL STUDIES.)

In the estrogen-plus-progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 vs. 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one and a trend toward decreasing relative risk was reported in years 2 through 5.

In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years), a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study (HERS)) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Participation in an open label extension of the original HERS trial (HERS II) was agreed to by 2,321 women. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of non-fatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

c.      Venous Thromboembolism

In the estrogen-alone substudy of WHI the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women taking conjugated estrogens compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years. (See CLINICAL STUDIES.)

In the estrogen-plus-progestin substudy of WHI, a statistically significant two-fold greater rate of VTE, was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES.)

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

a.      Endometrial cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risk of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations 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 of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

b.      Breast Cancer

In some studies, the use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) (see CLINICAL STUDIES). The results from observational studies are generally consistent with those of the WHI clinical trial.

Observational studies have also reported an increased risk of breast cancer for estrogen-plus-progestin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen-plus-progestin combination therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen-plus-progestin combinations, doses, or routes of administration.

In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95 % nCI 0.62-1.04).

In the estrogen-plus-progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of estrogen-alone or estrogen/progestin combination hormone therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI, 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen-plus-progestin compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for estrogen-plus-progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for estrogen-plus-progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen-plus-progestin group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen-alone and estrogen-plus-progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

1.      Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL), and impairment of glucose tolerance.

2.      Elevated blood pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

3.      Hypertriglyceridemia

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

4.      Impaired liver function and past history of cholestatic jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.

5.      Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored to maintain their free thyroid hormone levels in an acceptable range.

6.      Fluid retention

Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

7.      Hypocalcemia

Estrogens should be used with caution in individuals with severe hypocalcemia.

8.      Ovarian cancer

The estrogen-plus-progestin substudy of the WHI reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen-plus-progestin versus placebo was 1.58 (95% nCI, 0.77-3.24), but was not statistically significant. The absolute risk for estrogen-plus-progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen only products in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

9.      Exacerbation of endometriosis

Endometriosis may be exacerbated with administration of estrogens. Malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

10.      Exacerbation of other conditions

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

11.      Photosensitivity/Photoallergy

The effects of direct sun exposure to Divigel® application sites have not been evaluated in clinical trials. Nonclinical studies in guinea pigs showed no phototoxicity or photosensitivity. In addition, Divigel® has been shown to absorb light primarily at wavelengths below 290 nm. Therefore, Divigel® is not considered to have photosensitizing potential.

12.      Sunscreen application

Studies conducted using other approved topical estrogen gel products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. The effect of concomitant application of sunscreen and Divigel® to the same application site has not been clinically evaluated.

13.      Miscellaneous

Alcohol based gels are flammable. Avoid fire, flame, or smoking until the gel has dried.

Occlusion of the area where the topical drug product is applied with clothing or other barriers is not recommended until the gel is completely dried.

14.      Potential for Estradiol Transfer and Effects of Washing

There is a potential for drug transfer from one individual to the other following physical contact of Divigel® application sites. In a study to evaluate transferability to males from their female contacts, there was some elevation of estradiol levels over baseline in the male subjects, however, the degree of transferability in this study was inconclusive. Patients are advised to avoid skin contact with other subjects until the gel is completely dried. The site of application should be covered (clothed) after drying.

Washing the application site with soap and water 1 hour after application resulted in a 30 to 38% decrease in the mean total 24-hour exposure to estradiol. Therefore, patients should refrain from washing the application site for at least one hour after application.