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(Estradiol Transdermal System, USP)
Continuous Delivery for Twice Weekly Dosing
Revised: November 2009
Prescribing Information With Attached Patient Information Leaflet
WARNING: ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER.
Alora (Estradiol Transdermal System, USP) is designed to deliver estradiol continuously and consistently over a 3 or 4-day interval upon application to intact skin. Four strengths of Alora are available, having nominal in vivo delivery rates of 0.025, 0.05, 0.075, and 0.1 mg estradiol per day through skin of average permeability (inter-individual variation in skin permeability is approximately 20%). Alora has contact surface areas of 9 cm2, 18 cm2, 27 cm2, and 36 cm2 and contains 0.77, 1.5, 2.3, and 3.1 mg of estradiol, USP, respectively. The composition of the estradiol transdermal systems per unit area is identical. Estradiol, USP is a white, crystalline powder that is chemically described as estra-1,3,5(10)-triene-3, 17β-diol, has an empirical formula of C18H24O2 and has molecular weight of 272.39. The structural formula is:
Alora consists of three layers. Proceeding from the polyethylene backing film as shown in the cross-sectional view below, the adhesive matrix drug reservoir that is in contact with the skin consists of estradiol, USP and sorbitan monooleate dissolved in an acrylic adhesive matrix. The polyester overlapped release liner protects the adhesive matrix during storage and is removed prior to application of the system to the skin.
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.
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.
* Cmax and Cavg statistically different from abdomen
Table 1 provides a summary of the estradiol pharmacokinetic parameters studied during biopharmaceutic evaluation of Alora.
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.
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.
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 pre-dosing 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.
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, double-blind, placebo-controlled study in 355 hysterectomized, non-osteoporotic 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.
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:
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 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 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.)
INDICATIONS AND USAGE
Alora is indicated in:
Alora should not be used in individuals with any of the following conditions:
See BOXED WARNINGS.
The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.
1. Cardiovascular Disorders.
Estrogen and estrogen/progestin therapies have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
Coronary heart disease and stroke. In the Women’s Health Initiative (WHI) study an increased risk of stroke was observed in women receiving CE compared to placebo.
In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 women-years). The increase in risk was observed in Year 1 and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. (See CLINICAL PHARMACOLOGY, CLINICAL STUDIES.)
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 nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
Venous thromboembolism (VTE). In the Women’s Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving CE compared to placebo.
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL PHARMACOLOGY, 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.
2. Malignant Neoplasms.
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-fold 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 risks of 15 to 24-fold for 5 to 10 years or more, and 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.
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 WHI substudy of CE/MPA (see CLINICAL PHARMACOLOGY, CLINICAL STUDIES). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about 5 years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01 - 1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. 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 vs. 25 cases per 10,000 women-years, for CE/MPA 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 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA 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 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 self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
In the estrogen plus progestin WHIMS, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to CE/MPA or placebo. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n=2,229) and 21 women in the placebo group (0.9%, n=2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 - 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 vs. 22 cases per 10,000 women-years and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)
4. Gallbladder Disease.
A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures should be taken to reduce the serum calcium level.
6. Visual Abnormalities.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued.
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:
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.
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.
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 in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as patients with asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
7. Ovarian cancer.
The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA vs. placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA vs. placebo was 4.2 vs. 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
8. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogens. A few cases of 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.
B. Patient Information
See text of Patient Information. Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Alora.
C. Laboratory Tests
Estrogen administration should be guided by clinical response at the lowest dose for the treatment of vasomotor symptoms and vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.
D. Drug/Laboratory Test Interactions
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Long-term continuous administration of estrogen, with or without progestin, in women with or without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. ( See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
F. Pregnancy Category X
Alora should not be used during pregnancy. (See CONTRAINDICATIONS.)
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estrogen therapy. Estrogens are not indicated for the prevention of postpartum breast engorgement. Caution should be exercised when Alora is administered to a nursing woman.
H. Pediatric Use
Estrogen replacement therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.
I. Geriatric Use
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n=3,729) were 65 to 74 while 18% (n=803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a 2-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See BOXED WARNINGS and WARNINGS, Dementia.)
With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing Alora to determine whether those over 65 years of age differ from younger subjects in their response to Alora.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Incidence of adverse events > 2% of each treatment group is given in Table 5.
The following additional adverse reactions have been reported with estrogens and/or progestin therapy:
Serious ill effects have not been reported following acute ingestion of large doses of estrogen containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
Alora should be administered twice weekly, as instructed. The adhesive side of the Alora system should be placed on a clean, dry area of skin. The recommended application site is the lower abdomen. In addition, the upper quadrant of the buttocks or outer aspect of the hip may be used. Alora should not be applied to the breasts. The sites of application should be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub the system off. The system should be applied immediately after opening the pouch and removing the protective liner. The system should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges.
In the event that a system should fall off, the same system may be reapplied. If necessary, a new system may be applied to another site. The original treatment schedule should be maintained.
Initiation of Therapy
For treatment of moderate-to-severe vasomotor symptoms, vulvar and vaginal atrophy associated with the menopause, hypogonadism, castration, or primary ovarian failure, treatment is usually initiated with Alora 0.05 mg/day applied to the skin twice weekly. The lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.
For the prevention of postmenopausal osteoporosis, the minimum dose of Alora that has been studied and shown to be effective is 0.025 mg/day applied to the skin twice weekly. Bone mineral density measurements should be repeated to monitor treatment efficacy. The dosage may be increased as necessary, depending on bone mineral density and adverse events.
In women who are not currently taking oral estrogens or in women switching from topical therapy or another transdermal estradiol therapy, treatment with Alora can be initiated at once. In women who are currently taking oral estrogens, treatment with Alora should be initiated 1 week after withdrawal of oral therapy or sooner if menopausal symptoms reappear in less than 1 week.
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Alora may be administered in a continuous regimen in patients who do not possess an intact uterus. In those patients with an intact uterus who are not using concomitant progestin therapy, Alora can be administered on a cyclic schedule (e.g., 3 weeks of therapy followed by 1 week without) for the treatment of postmenopausal symptoms. However, no studies have been conducted using this intermittent regimen for the prevention of postmenopausal osteoporosis.
Alora (Estradiol Transdermal System, USP) 0.025 mg/day. Each 9 cm2 system contains 0.77 mg of estradiol, USP for nominal delivery of 0.025 mg of estradiol per day when dosed in a twice weekly regimen.
NDC 52544-884-08 Patient Calendar Box of 8 Systems
Alora (Estradiol Transdermal System, USP) 0.05 mg/day. Each 18 cm2 system contains 1.5 mg of estradiol, USP for nominal delivery of 0.05 mg of estradiol per day when dosed in a twice weekly regimen.
NDC 52544-471-08 Patient Calendar Box of 8 Systems
Alora (Estradiol Transdermal System, USP) 0.075 mg/day. Each 27 cm2 system contains 2.3 mg of estradiol, USP for nominal delivery of 0.075 mg of estradiol per day when dosed in a twice weekly regimen.
NDC 52544-472-08 Patient Calendar Box of 8 Systems
Alora (Estradiol Transdermal System, USP) 0.1 mg/day. Each 36 cm2 system contains 3.1 mg of estradiol, USP for nominal delivery of 0.1 mg of estradiol per day when dosed in a twice weekly regimen.
NDC 52544-473-08 Patient Calendar Box of 8 Systems
Store at 20-25°C (68-77°F). [See USP controlled room temperature.]
Do not store unpouched. Apply immediately upon removal from the protective pouch.
Discard used Alora in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.
Address medical inquiries to:
Revised: November 2009
Read this PATIENT INFORMATION before you start using Alora (ah-LORE-ah) and read what you get each time you refill Alora. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ALORA (AN ESTROGEN HORMONE)?
What is Alora?
Alora is a patch that contains the estrogen hormone estradiol. When applied to the skin as directed below, the Alora patch releases estrogen through the skin into the abdomen.
What is Alora used for?
Alora is used after menopause to:
Who Should Not Use Alora
Do not use Alora if you:
Tell your healthcare provider:
What Are the Possible Side Effects of Alora?
Less common but serious side effects include:
These are some of the warning signs of serious side effects:
Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.
Common side effects include:
Other side effects include:
These are not all the possible side effects of Alora. For more information, ask your healthcare provider or pharmacist.
What Can I Do to Lower My Chances of Getting a Serious Side Effect with Alora?
How should I use Alora?
Before you begin, read all the information in these 5 steps.
Step 1. Choose your schedule for twice-a-week application.
Put on a new patch twice a week. Use one of the schedules on the inside flap of the patch box.
For example, if you apply your first patch on Sunday, take that patch off on Wednesday and put on a new one. Stay on this schedule as long as you use Alora. To help remind yourself, mark the schedule on the inside flap of the patch box. Put a check next to the first day you apply the patch. When you change your patch, don’t put the new one in the same place. To help reduce the chance of skin redness or irritation, wait at least one week before you reuse a spot.
Step 2. Before you apply the patch make sure the skin at the spot is:
Step 3. Choose a spot for the patch
Step 4. How to apply the patch
Press for at least 10 seconds to make sure the patch will stay in place. Be sure all of it sticks to your skin, even around the edges.
To help the patch stay in place:
Step 5. Removing the patch
The skin under the old patch may look pink, but the color should fade away soon. In some cases, the skin may itch or look red; this may last from a couple of hours to a couple of days. Most of the time this is minor, and goes away by itself. But if it bothers you a lot or lasts longer than a few days, call your healthcare provider.
For Best Results, Stay with Your Patch Program
How should I store Alora?
Store at 20-25°C (68-77°F). [See USP controlled room temperature.] Do not store patches outside of their pouches. Apply the patch as soon as you take it out of the protective pouch.
Discard used Alora in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.
General Information about the safe and effective use of Alora
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Alora for conditions for which it was not prescribed. Your healthcare provider has prescribed this drug for you and you alone. Do not give the drug to anyone else. It may harm them. Keep Alora out of the reach of children.
This leaflet provides a summary of the most important information about Alora. If you would like more information, talk with your healthcare provider. You can ask for information about Alora that is written for health professionals.
What are the ingredients in Alora?
Each patch contains estradiol, USP as the active component. Inactive components of each patch include sorbitan monooleate, NF; acrylic adhesive; polyethylene film; and siliconized polyester film.
Address medical inquiries to:
Revised: November 2009
Revised: 06/2010 Watson Pharma, Inc.
Reproduced with permission of U.S. National Library of Medicine
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