"The U.S. Food and Drug Administration today approved Osphena (ospemifene) to treat women experiencing moderate to severe dyspareunia (pain during sexual intercourse), a symptom of vulvar and vaginal atrophy due to menopause.
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.
The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy.
Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process, the rate of diffusion across the stratum corneum being the principal factor. Alora presents sufficient concentration of estradiol to the surface of the skin to maintain continuous transport over the 3 to 4 day dosing interval.
Direct measurement of total absorbed dose of estradiol through analysis of residual estradiol content of systems worn over a continuous 4-day interval during 251 separate occasions in 123 postmenopausal women demonstrated that the average daily dose absorbed from Alora was 0.003 ± 0.001 mg estradiol per cm² active surface area. The nominal mean in vivo daily delivery rates of estradiol calculated from these data are 0.027 mg/day, 0.054 mg/day, 0.081 mg/day, and 0.11 mg/day for the 9 cm², 18 cm², 27 cm², and 36 cm² Alora, respectively.
In another study, 20 women also were treated with three consecutive doses of Alora 0.05 mg/day, Alora 0.075 mg/day and Alora 0.1 mg/day on abdominal application sites. Mean steady-state estradiol serum concentrations observed over the dosing interval are shown in Figure 1.
Figure 1: Mean steady-state estradiol serum
concentration during the third twice weekly dose of Alora 0.1 mg/day, Alora 0.075
mg/day, and Alora 0.05 mg/day in 20 postmenopausal women.
In a single dose randomized crossover study conducted to compare the effect of site of Alora application, 31 postmenopausal women wore single Alora 0.05 mg/day for 4-day periods on the lower abdomen, upper quadrant of the buttocks, and outside aspect of the hip. The estradiol serum concentration profiles are shown in Figure 2.
Figure 2: Mean estradiol serum concentrations
during a single 4-day wearing of Alora 0.05 mg/day applied by 31 postmenopausal
women to the lower abdomen, upper quadrant of the buttocks or outer aspect of
Table 1 provides a summary of the estradiol pharmacokinetic parameters studied during biopharmaceutic evaluation of Alora.
Table 1 : Mean (SD) Pharmacokinetic Profile of Alora
Over an 84-hour Dosing Interval.
|Alora (mg/day)||Application Site||N||Dosing||Cmax (pg/ml)||Cmin (pg/ml)||Cavg (pg/ml)||CL (L/hr)|
|0.075||Abdomen||20||Multiple||120(60)||53 (23)||86 (40)||53(12)|
|0.1||Abdomen||42||Multiple||144(57)||58 (20)||98 (38)||61 (18)|
|0.05||Abdomen||31||Single||53 (23)||-||41 (18)||69 (22)|
|Buttock||31||Single||67 (45)||-||45(21)||66 (23)|
|Hip*||31||Single||69 (30)||-||48 (17)||62 (18)|
|*Cmax and Cavg statistically different from abdomen|
Steady-state estradiol serum concentrations were measured in two well-controlled clinical trials in the treatment of menopausal symptoms of 3 month duration (Studies 1 and 2), and one trial in the prevention of postmenopausal osteoporosis of 2 year duration (Study 3). Table 2 provides a summary of these data.
Table 2: Mean (SD) steady-state estradiol serum
concentrations (pg/ml) in clinical trials of 3 month (Studies 1 and 2) and 2
year (Study 3) duration.
|Alora (mg/day)||Study 1||Study 2||Study 3|
|0.05||46.9 (38.5)||38.8 (38.0)||42.6 (23.7)|
|0.1||99.2 (77.0)||97.0 (87.5)||-|
In a 2-year, randomized, double-blind, placebo-controlled, prevention of postmenopausal osteoporosis study in 355 hysterectomized women, the average baseline-adjusted steady-state estradiol serum concentrations were 18.6 pg/ml (45 patients) for the 0.025 mg/day dose, 35.9 pg/ml (47 patients) for the 0.05 mg/day dose, and 50.1 pg/ml (46 patients) for the 0.075 mg/day dose. These values were linearly related and dose proportional.
No specific investigation of the tissue distribution of estradiol absorbed from Alora in humans has been conducted. 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 gut 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 apparent mean (SD) serum half-life of estradiol determined from biopharmaceutic studies conducted with Alora is 1.75 ± 2.87 hours.
Alora has been studied only in healthy postmenopausal women (approximately 90% Caucasian). There are no long term studies in postmenopausal women with an intact uterus. No pharmacokinetic studies were conducted in other 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, phenytoin, carbamazepine, rifampin and dexamethasone 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 cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
The adhesion potential of Alora was evaluated in a randomized clinical trial involving 408 healthy postmenopausal women who wore placebo systems corresponding to the 18 cm² size Alora. The placebos were applied twice weekly for 4 weeks on the lower quadrant of the abdomen. It should be noted that the lower abdomen, the upper quadrant of the buttocks or outer aspect of the hip are the approved sites of application for Alora. Subjects were instructed not to do strenuous activities, take baths, use hot tubs or swim. In 968 observations, there was a partial or complete adhesion rate of approximately 97%. The total detachment rate was approximately 3%. Adhesion potentials of the 9 cm², 27 cm² and 36 cm² sizes of Alora have not been studied.
Effects On Vasomotor Symptoms
Efficacy of Alora has been studied in a double blind/double dummy, randomized, parallel group, placebo-controlled trial involving a total of 268 postmenopausal women over a 12-week dosing period. Only women having estradiol and FSH serum concentrations in the postmenopausal range and who exhibited a weekly average of at least 60 moderate to severe hot flushes during the screening period were enrolled in the studies.
Patients received Alora 0.05 mg/day and a placebo system, or Alora 0.1 mg/day and a placebo system, or two placebo systems dosed twice weekly over a 12-week duration. Measures of efficacy included mean reduction in weekly number of moderate to severe vasomotor symptoms when compared to the mean baseline average determined during a 2-week predosing screening period. Alora was shown to be statistically better than placebo at Weeks 4 and 12 for relief of both the frequency (see Table 3) and severity of vasomotor symptoms.
Table 3 : Mean Change from Baseline in
Frequency of Moderate to Severe Vasomotor Symptoms for Alora Compared to
|Week of Therapy||Mean Change from Baseline|
|Alora 0.05 mg/day
N = 87
Baseline = 90
|Alora 0.1 mg/day
N = 91
Baseline = 85
N = 90
Baseline = 92
|*Indicates statistically significant differences between both strengths of Alora and placebo using an ANCOVA model adjusting for baseline.|
Effects On Vulvar And Vaginal Atrophy
Vaginal cytology was obtained pre-dosing and at last visit in 54 women treated with Alora 0.05 mg/day, in 45 women treated with Alora 0.1 mg/day, and in 46 women in the placebo group. Superficial cells increased by a mean of 18.7%, 23.7%, and 8.7% for the Alora 0.05 mg/day, Alora 0.1 mg/day, and placebo groups, respectively. Corresponding reductions in basal/parabasal and intermediate cells were also observed.
Effects On Bone Mineral Density
Lumbar spine bone mineral density (BMD) was measured by DEXA in a 2-year, randomized, multi-center, doubleblind, placebo-controlled study in 355 hysterectomized, nonosteoporotic women (i.e., T-scores > -2.5). Eighty-six percent of the women were Caucasian, the mean age was 53.2 years (range 26 to 69), and the average number of years since menopause (natural or surgical) was not determined. Three Alora doses (0.025 mg/day, 0.05 mg/day, and 0.075 mg/day) were compared to placebo in terms of the % change in BMD from baseline to Year 2. The systems were applied every 3 or 4 days on alternate sides of the lower abdomen. All patients received 1000 mg of oral elemental calcium daily. The average baseline lumbar spine T-score was -0.64 (range -2.7 to 3.8). The % changes in BMD from baseline are illustrated in Figure 3.
Figure 3: Mean % change in BMD from baseline at 1 and 2 years after initiation of therapy with Placebo and Alora 0.025, 0.05, and 0.075 mg/day in the completer and intent-to-treat population with last observation carried forward (LOCF).
A total of 196 patients (44 - 0.025 mg/d, 49 - 0.05 mg/d, 45 - 0.075 mg/d, and 58 - placebo) were included in the completer population compared with 258 patients (59 - 0.025 mg/d, 64 - 0.05 mg/d, 63 - 0.075 mg/d, and 72 - placebo) in the intent-to-treat, last observation carried forward population.
All Alora doses were statistically superior to placebo for the primary endpoint, percent change in BMD from baseline. The mean 2-year (LOCF) percent changes in BMD for 0.025 mg/d, 0.05 mg/d, 0.075 mg/d, and placebo were 1.45%, 3.39%, 4.24%, and - 0.80% respectively.
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 either the use of 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 cause. 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 4 below:
Table 4: Relative and Absolute Risk Seen in the
CE/MPA Substudy of WHIa.
|Eventc||Relative Risk CE/MPA vs. placebo at 5.2 years (95% CI*)||Placebo
N = 8102
N = 8506
|Absolute Risk per 10,000 Person-years|
|CHD events||1.29 (1.02-1.63)||30||37|
|Noil-fatal Ml||1.32 (1.02-1.72)||23||30|
|Invasive breast cancerb||1.26 (1.00-1.59)||30||38|
|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
* normal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the “global index,” absolute excess risks per 10,000 person-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 womenyears. There was no difference between the groups in terms of all-cause mortality [see BOXED WARNINGS and 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 age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 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 and PRECAUTIONS, Geriatric Use].
Last reviewed on RxList: 1/30/2017
This monograph has been modified to include the generic and brand name in many instances.
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