|
Vivelle®
T2004-67
101985-3
Vivelle ®
estradiol transdermal system
Continuous delivery for twice-weekly application
Rx only
Prescribing Information
DESCRIPTION
The Vivelle® (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin.
Five systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via skin of average permeability. Each corresponding system having an active surface area of 7.25, 11.0, 14.5, 22.0, or 29.0 cm2 contains 2.17, 3.28, 4.33, 6.57, or 8.66 mg of estradiol USP, respectively. The composition of the systems per unit area is identical.
Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17ß-diol.
The structural formula is
The molecular formula of estradiol is C18H24O2. The molecular weight is 272.39.
The Vivelle system comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent flexible film consisting of an ethylene vinyl alcohol copolymer film, a polyurethane film, urethane polymer and epoxy resin, (2) an adhesive formulation containing estradiol USP, acrylic adhesive, polyisobutylene, ethylene vinyl acetate copolymer, 1,3 butylene glycol, styrene-butadiene rubber, oleic acid NF, lecithin, propylene glycol, bentonite NF, mineral oil USP, and dipropylene glycol, and (3) a polyester release liner that is attached to the adhesive surface and must be removed before the system can be used.
The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive.
|
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 seen in postmenopausal women.
Pharmacokinetics
Absorption
In a multiple-dose study consisting of three consecutive patch applications of the Vivelle system, which was conducted in 17 healthy, postmenopausal women, blood levels of estradiol and estrone were compared following application of these units to sites on the abdomen and buttocks in a crossover fashion. Patches that deliver nominal estradiol doses of approximately 0.0375 mg/day and 0.1 mg/day were applied to abdominal application sites while the 0.1 mg/day doses were also applied to sites on the buttocks. These systems increased estradiol levels above baseline within four hours and maintained respective mean levels of 25 and 79 pg/mL above baseline following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were observed following application to the buttocks. At the same time, increases in estrone plasma concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and 61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained slightly above baseline at 12 hours following removal of the patches in this study, results from another study show these levels to return to baseline values within 24 hours following removal of the patches.
The figure (see Figure 1) illustrates the mean plasma concentrations of estradiol at steady state during application of these patches at four different dosages.
 Figure 1Steady-State Estradiol Plasma Concentrationsfor Systems Applied to the AbdomenNonbaseline-Corrected Levels
The corresponding pharmacokinetic parameters are summarized in Table 1 below.
Table 1 Steady-State Estradiol Pharmacokinetic Parameters for Systems Applied to the Abdomen (mean ± standard deviation) Nonbaseline-Corrected Data* Dosage
(mg/day) | Cmax†
(pg/mL) | Cavg‡
(pg/mL) | Cmin (84 hr)§
(pg/mL) |
| 0.0375 |
| 46 ± 16 |
| 34 ± 10 |
| 30 ± 10 |
| 0.05 |
| 83 ± 41 |
| 57 ± 23# |
| 41 ± 11# |
| 0.075 |
| 99 ± 35 |
| 72 ± 24 |
| 60 ± 24 |
| 0.1 |
| 133 ± 51 |
| 89 ± 38 |
| 90 ± 44 |
| 0.1 |
| 145 ± 71 |
| 104 ± 52 |
| 85 ± 47 |
*Mean baseline estradiol concentration = 11.7 pg/mL
†Peak plasma concentration
‡Average plasma concentration
§Minimum plasma concentration at 84 hr
#Measured over 80 hr
¶Applied to the buttocks
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.
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 gut 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.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Studies conducted with the Vivelle system show the drug has an apparent mean half-life of 4.4 ± 2.3 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours.
Special Populations
Vivelle was only investigated in postmenopausal women.
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.
Adhesion
Data showing the number of systems in controlled studies that required replacement due to inadequate adhesion is not available.
|
Clinical Studies
In two controlled clinical trials of 356 subjects, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and 12 of treatment. In this original study, the 0.0375 and 0.05 mg doses, however, did not differ from placebo until approximately Week 6; therefore, an additional 12-week placebo-controlled study in 255 patients was performed to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 patients was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in the figure below. (See Figure 2.)
 Figure 2Mean (SD) Change from Baseline in Mean Daily Number of Flushesfor Vivelle 0.0375 mg Versus Placebo in a 12-Week Trial
The 0.0375-mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Week 4 and maintained efficacy through Weeks 8 and 12 of treatment. The following doses of Vivelle: 0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg, are effective for the control of vasomotor symptoms.
Efficacy and safety of the Vivelle system in the prevention of postmenopausal osteoporosis have been studied in a 2-year double-blind, randomized, placebo-controlled, parallel group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within five years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within two standard deviations of average peak bone mass, i.e., =0.827 g/cm2) were enrolled in this study; 194 patients were randomized to one of the four doses of Vivelle (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 patients to placebo. Over two years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study.
The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized (61%) or non-hysterectomized (39%) women with a mean age of 52.0 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89%) of randomized subjects (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Patients were given supplemental dietary calcium (1000 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All Vivelle doses were significantly superior to placebo (p<0.05) at all time points with the exception of Vivelle 0.05 mg/day at six months. The highest dose of Vivelle was superior to the three lower doses. There were no statistically significant differences in pairwise comparisons among the three lower doses. (See Figure 3.)
 Figure 3Bone Mineral Density - AP Lumbar SpineLeast Squares Means of Percentage Change from BaselineAll Randomized Patients with at Least One Post-Baseline Assessment Available with Last Post-Baseline Observation Carried Forward
Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to placebo (p<0.05) at 24 months. The highest Vivelle dose was superior to placebo at all time points. A mixture of significant and non-significant results were obtained for the lower dose groups at earlier time points. The highest Vivelle dose was superior to the three lower doses, and there were no significant differences among the three lower doses at this skeletal site. (See Figure 4.)
 Figure 4Bone Mineral Density - Femoral NeckLeast Squares Means of Percentage Change from BaselineAll Randomized Patients with at Least One Post-Baseline Assessment Available with Last Post-Baseline Observation Carried Forward
The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-telopeptides of type 1 collagen (a marker of bone resorption) decreased numerically in most of the active treatment groups relative to baseline. However, the decreases in both markers were inconsistent across treatment groups and the differences between active treatment groups and placebo were not statistically significant.
Women’s Health Initiative Studies
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) 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 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, 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 CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79, 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 2 below.
Table 2 Relative and Absolute Risk Seen in the CE/MPA Substudy of WHIa | Eventc | Relative Risk
CE/MPA vs. | Placebo
n= 8102 | CE/MPA
n= 8506 |
| Placebo at 5.2 Years
(95% CI*) | Absolute Risk per
10,000 Women-Years |
| CHD Events | 1.29 (1.02-1.63) | 30 | 37 |
| Nonfatal MI | 1.32 (1.02-1.72) | 23 | 30 |
| CHD Death | 1.18 (0.70-1.97) | 6 | 7 |
| Invasive Breast Cancerb | 1.26 (1.00-1.59) | 30 | 38 |
| Stroke | 1.41 (1.07-1.85) | 21 | 29 |
| Pulmonary Embolism | 2.13 (1.39-3.25) | 8 | 16 |
| Colorectal Cancer | 0.63 (0.43-0.92) | 16 | 10 |
| Endometrial Cancer | 0.83 (0.47-1.47) | 6 | 5 |
| Hip Fracture | 0.66 (0.45-0.98) | 15 | 10 |
Death Due to Causes Other
Than the Events Above | 0.92 (0.74-1.14) | 40 | 37 |
| Global Indexc | 1.15 (1.03-1.28) | 151 | 170 |
| Deep Vein Thrombosisd | 2.07 (1.49-2.87) | 13 | 26 |
| Vertebral Fracturesd | 0.66 (0.44-0.98) | 15 | 9 |
| Other Osteoporotic Fracturesd | 0.77 (0.69-0.86) | 170 | 131 |
a Adapted from JAMA, 2002: 288: 321-333
b Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
d Not included in global index
* Nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the “global index”, absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Women’s Health Initiative Memory Study
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, 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 oral CE/MPA (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of four years, 40 women in the estrogen/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 to 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 WARNINGS and WARNINGS, Dementia.)
|
