PRESCRIBING INFORMATION

Alora estradiol transdermal system is designed to deliver 17(beta)-estradiol continuously and consistently over a 3 or 4-day interval upon application to intact skin. Three strengths of Alora systems are available, having nominal in vivo delivery of 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 systems have contact surface areas of 18, 27, and 36 cm ² and contain 1.5, 2.3, and 3.0 mg of estradiol, USP, respectively. The composition of the systems per unit active surface area is identical. Estradiol, USP (17(beta)-estradiol) is a white, crystalline powder that is chemically described as estra-1,3,5(10)-triene-3,17(beta)-diol, has an empirical formula of C ₁₈ H ₂₄ O ₂ and has molecular weight of 272.37. The structural formula is:

The Alora system 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.

Alora provides systemic estrogen replacement therapy by delivering estradiol, the major estrogenic hormone secreted by the human ovary, through the area of intact skin covered by the system. Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, Fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. They also contribute to the shaping of skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals.

Circulating estrogen concentration modulates the pituitary secretion of the gonadotrophins luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism and estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in the postmenopausal woman. In a multiple dose study in 22 postmenopausal women, Alora 0.1 mg/day reduced circulating concentrations of LH and FSH by 34% and 45%, respectively, by the end of the third dose.

Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to a small amount of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone (especially in its sulfate ester form) is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor level.

Estrogen drug products act by regulating the transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to, and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn leads to the observed effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and in bone of women.

Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of systemic absorption of injected oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks.

Administered estrogens and their esters are handled within the body essentially the same as the endogenous hormones. Metabolic conversion of estrogens occurs primarily in the liver (first pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and non-esterified forms. Although naturally-occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile and then reabsorbed from the intestine. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to non-estrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).

Loss of ovarian estradiol secretion after menopause can result in instability of thermoregulation, causing hot flushes associated with sleep disturbance and excessive sweating, and urogenital atrophy, causing dyspareunia and urinary incontinence. Estradiol replacement therapy alleviates many of these symptoms of estradiol deficiency in the menopausal woman.

Transdermal administration of Alora produces mean serum concentrations of estradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. The pharmacokinetics and metabolism of transdermally administered estradiol using Alora have been evaluated in a total of 123 healthy postmenopausal women in three dose-range finding studies and in three definitive studies.

Absorption

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 four 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 cm ² active surface area. The nominal mean in vivo daily delivery rates of estradiol calculated from these data are 0.054 mg/day, 0.081 mg/day, and 0.11 mg/day for the 18 cm ² , 27 cm ² , and 36 cm ² Alora systems, respectively.

In one multiple dose study, 22 postmenopausal women were treated with three consecutive Alora 0.1 mg/day systems on abdominal sites of application in a twice weekly dosing regimen and 3 consecutive Estraderm® ¹ 0.1 estradiol transdermal systems in the same dosing regimen. During the third Alora dose, serum concentrations of estradiol increased above steady state baseline within 4 hours, achieved mean maximum concentration of 133 pg/ml within 18-24 hours, and remained relatively constant between 70 and 100 pg/ml until system removal at 96 hours. In contrast, Estraderm 0.1 mg/day produced higher fluctuations in estradiol serum concentrations, achieving and maintaining serum concentrations greater than 70 pg/ml only during the first 36 hours of the dosing period. Thereafter, serum estradiol concentrations declined steadily to a mean level of 22 pg/ml at system removal at 96 hours of the third dosing interval. The mean steady state estradiol serum concentration profiles for Alora 0.1 mg/day and Estraderm 0.1 mg/day are shown in Figure 1.

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 2.

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 four 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 3.

Table 1 provides a summary of the estradiol pharmacokinetic parameters studied during biopharmaceutic evaluation of Alora .

Distribution

No specific investigation of the tissue distribution of estradiol absorbed from Alora in humans has been conducted. However, a significant body of literature exists that indicates that estradiol is widely distributed in the body and is generally found in higher concentrations in the sex hormone target organs. Estradiol in blood is distributed between free estradiol, albumin bound estradiol, and sex hormone binding globulin (SHBG) bound estradiol. Serum concentrations reported here are expressed as total estradiol concentrations.

Metabolism

Since transdermally absorbed estradiol is not subject to first pass liver metabolism, the ratio of serum concentrations of estradiol to either of its major metabolites, estrone or estrone sulfate, is significantly greater than that seen for the oral route of administration. The clinical relevance of the estradiol to estrone ratio is presently unknown.

In controlled clinical trials using Alora compared to orally administered conjugated equine estrogens (CEE), the serum concentrations of estradiol and its metabolites were measured after 12 weeks therapy and are given in Table 2. The overall mean (SD) ratio of estradiol to estrone was 1.26 (0.80) for Alora and was 0.30 (0.39) for CEE.

Elimination

No specific studies of elimination of estradiol have been performed using Alora . However, elimination of estradiol is known to be primarily through liver metabolism and conjugation to more hydrophilic compounds such as sulfates and glucuronides which are then cleared through renal elimination. Because estradiol has a short half-life, transdermal administration of estradiol allows for rapid decline in blood levels after Alora is removed. The apparent mean (SD) serum half-life of estradiol determined from biopharmaceutic studies conducted with Alora is 1.75 ± 2.87 hours.

Special Populations

Alora has been studied only in postmenopausal women.

CONTROLLED CLINICAL STUDIES

Efficacy and safety of Alora have been studied in two double blind/double dummy, randomized, parallel group trials involving a total of 594 postmenopausal women over a 12 week dosing period. In both studies, measures of efficacy included reduction in weekly number of moderate-to-severe vasomotor symptoms when compared to a weekly baseline average determined during a 2-week pre-dosing screening 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.

In a positive control study, each patient received unopposed estrogen for a duration of 12 weeks in the form of Alora 0.05 mg/day, Alora 0.1 mg/day, administered twice weekly; or once daily oral administration of conjugated equine estrogens (CEE) 0.625 mg, or CEE 1.25 mg. In this study, the population was primarily caucasian (88%), had a mean age of 50.4 years (range 29-75 years), and had undergone either natural menopause (46%) or surgical menopause (54%) at an average age of 42.5 years (range 19-62 years). Mean baseline frequency of moderate-to-severe vasomotor symptoms was 95 per week in the overall population studied. Mean percent reduction in frequency of moderate-to-severe hot flushes is shown in Table 3.

In a placebo-controlled study, each patient received either Alora 0.05 mg/day, Alora 0.1 mg/day, or matching placebo unopposed and dosed twice weekly over a 12 week duration. In this study, the population was also primarily caucasian (88%), had a mean age of 50.9 years (range 31-70 years), and had undergone either natural menopause (44%) or surgical menopause (56%) at an average age of 43.0 years (range 16-58 years). Mean baseline frequency of moderate-to-severe vasomotor symptoms was 89 per week in the overall population studied. Mean percent reduction in frequency of moderate-to-severe hot flushes is shown in Table 4.

In the two clinical trials, vaginal cytology was obtained pre-dosing and at last visit in a total of 103 women treated with Alora 0.05 mg/day, in 88 women treated with Alora 0.1 mg/day and in 46 women in the placebo group. Superficial cells increased by a mean of 15.4%, 26.6% and 8.1% 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.

Alora is indicated in:

1. Treatment of moderate-to-severe vasomotor symptoms associated with the menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression which might occur during menopause and they should not be used to treat these conditions.
2. Treatment of vulval and vaginal atrophy.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.

CONTRAINDICATIONS

Estrogens should not be used in individuals with any of the following conditions:

1. Known or suspected pregnancy (see Boxed Warning ): Estrogens may cause fetal harm when administered to a pregnant woman.
2. Undiagnosed abnormal genital bleeding;
3. Known or suspected cancer of the breast;
4. Known or suspected estrogen-dependent neoplasia;
5. Active thrombophlebitis, or thromboembolic disorders.
6. Known hypersensitivity to any of the components of Alora .

1. Induction of malignant neoplasms:
   Endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 fold greater than in nonusers, 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 one year. The greatest risk appears associated with prolonged use--with increased risks of 15 to 24-fold for five to ten years or more. In three studies, persistence of risk was demonstrated for 8 to over 15 years after cessation of estrogen treatment. In one study a significant decrease in the incidence of endometrial cancer occurred six months after estrogen withdrawal. Concurrent progestin therapy may offset this risk but the overall health impact in postmenopausal women is not known (see PRECAUTIONS ).
   Breast cancer:   Some studies have suggested a possible increased incidence of breast cancer in those women taking estrogen therapy at higher doses or for prolonged periods of time. While the majority of studies have not shown an increased risk of breast cancer in women who have ever used estrogen replacement therapy, some have reported a moderately increased risk (relative risks of 1.3-2.0) in those taking higher doses or those taking lower doses for prolonged periods of time, especially in excess of 10 years. On the other hand, other studies have not shown this relationship.
   Congenital lesions with malignant potential. Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive tract disorders, and possibly other birth defects. Studies of women who received DES during pregnancy have shown that female offspring have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix, and clear cell vaginal cancer later in life; male offspring have an increased risk of urogenital abnormalities and possibly testicular cancer later in life. Although some of these changes are benign, others are precursors of malignancy.
2. Gallbladder disease: Two studies have reported a 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving oral estrogen replacement therapy, similar to the 2-fold increase previously noted in users of oral contraceptives.
3. Cardiovascular disease: 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 risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. These risks cannot necessarily be extrapolated from men to women. However, to avoid the theoretical cardiovascular risk to women caused by high estrogen doses, the dose for estrogen replacement therapy should not exceed the lowest effective dose.
4. Elevated blood pressure: Occasional blood pressure increases during estrogen replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often, blood pressure has remained the same or has dropped. One study showed that postmenopausal estrogen users have higher blood pressure than nonusers. Two other studies showed slightly lower blood pressure among estrogen users compared to nonusers. Postmenopausal estrogen use does not increase the risk of stroke. Nonetheless, blood pressure should be monitored at regular intervals during estrogen use.
5. Hypercalcemia: Administration of estrogens 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.

PRECAUTIONS

A. General

1. Addition of a progestin: Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Morphologic and biochemical studies of endometrium suggest that 10 to 14 days of progestin are needed to provide maximal maturation of the endometrium and to reduce the likelihood of hyperplastic changes.
   There are, however, possible risks which may be associated with the use of progestins in estrogen replacement regimens. These include:
   
   1. adverse effects on lipoprotein metabolism (lowering HDL and raising LDL) which could diminish the purported cardioprotective effect of estrogen therapy (see PRECAUTIONS below).
   2. impairment of glucose tolerance; and
   3. possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiological data are available to address this point (see PRECAUTIONS below).
      The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues will require further study before they are clarified.
2. Cardiovascular risk: A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestins on this putative benefit is not yet known. In recent years, many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral estrogen replacement therapy without added progestins and a decrease in cardiovascular disease in women. Although most of the observational studies which assess this statistical association have reported a 20% to 50% reduction in coronary heart disease risk and associated mortality in estrogen users, the following should be considered when interpreting these reports:
   
   1. Because only one of these studies was randomized and it was too small to yield statistically significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced risk of coronary disease cannot be attributed with certainty to estrogen replacement therapy. It may instead have been caused by life-style and medical characteristics of the women studied with the results that healthier women were selected for estrogen therapy. In general, treated women were of higher socioeconomic and educational status, more slender, more physically active, more likely to have undergone surgical menopause, and less likely to have diabetes than the untreated women. Although some studies attempted to control for these selection factors, it is common for properly designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus, ongoing and future large-scale randomized trials may fail to confirm this apparent benefit.
   2. Current medical practice often includes the use of concomitant progestin therapy in women with intact uteri. (See PRECAUTIONS and ). While the effects of added progestins on the risk of ischemic heart disease are not known, all available progestins reverse at least some of the favorable effects of estrogens on HDL and LDL levels.
   3. While effects of added progestins on the risk of breast cancer are also unknown, available epidemiological evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer incidence that has been reported with prolonged estrogen replacement therapy (see above).
      Because relatively long-term use of estrogens by a woman with a uterus has been shown to increase the risk of endometrial cancer, physicians often recommend that women who are deemed candidates for hormone replacement should take progestins as well as estrogens. When considering prescribing concomitant estrogens and progestins for hormone replacement therapy, physicians and patients are advised to carefully weigh the potential benefits and risks of the added progestin. Large-scale randomized, placebo-controlled, prospective clinical trials are required to clarify these issues.
3. Physical Examination: A complete medical and family history should be taken before initiation of any estrogen therapy. The pre-treatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen and pelvic organs, as well as a cervical Papanicolaou test. As a general rule, estrogen should be prescribed for no longer than 1 year without another physical examination being performed.
4. Hypercoagulability: Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears dose-and duration-dependent and is less pronounced than that associated with oral contraceptive use. Also postmenopausal women tend to have increased coagulation parameters at baseline compared to premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies (primarily of oral conjugated estrogen users) report no such increase. There is insufficient information on hypercoagulability in women who have had previous thromboembolic disease.
5. Familial hyperlipoproteinemia: Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.
6. Fluid retention: Because estrogens may cause some degree of fluid retention, careful observation is required when conditions that might be influenced by this factor are present (e.g., asthma, epilepsy, migraine, and cardiac or renal dysfunction).
7. Uterine bleeding and mastodynia: Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.
8. Impaired liver function. Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.

B. Information for the Patient

See Patient Package Insert printed below.

C. Laboratory Tests

Estrogen administration should generally be guided by clinical response at the smallest dose, rather than laboratory monitoring, for relief of symptoms for those indications in which symptoms are observable.

D. Drug/Laboratory Test Interactions

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
6. Reduced response to the metapyrone test.
7. Reduced serum folate concentration.

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 (see CONTRAINDICATIONS and ).

F. Pregnancy Category X

Estrogens should not be used during pregnancy (see CONTRAINDICATIONS and Boxed ).

G. Nursing Mothers

As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.

H. Geriatric Use

The safety and effectiveness in geriatric patients (over age 65) have not been established.

ADVERSE REACTIONS

Alora has been studied in two well-controlled clinical trials. One study compared twice weekly dosing of Alora at 0.05 mg/day and 0.1 mg/day to once daily dosing of 0.625 mg and 1.25 mg of orally administered conjugated equine estrogens (CEE) in the intent-to-treat population of 321 postmenopausal women. In addition, the same Alora doses were studied in a placebo-controlled study in an intent-to-treat population of 273 postmenopausal women. Incidence of adverse experiences > 5% of each treatment group is given below in Table 5.

Vaginal Bleeding

Overall in these two studies, 232 of the 594 patients enrolled possessed a partially or fully intact uterus. Fifty five (24%) of these women experienced at least one instance of vaginal bleeding during treatment. Of those patients receiving placebo, 12.9% of patients experienced at least one vaginal bleeding episode. The incidence of vaginal bleeding among estrogen treated patients increased with increasing dose of all estrogen treatments: 8.7% of those receiving Alora 0.05 mg/day, 20.0% of those receiving CEE 0.625 mg/day, 33.3% of those receiving CEE 1.25 mg/day, and 33.3% of those receiving Alora 0.1 mg/day.

Skin Irritation

In the total population of 594 postmenopausal women exposed to either placebo and/or Alora systems in these studies, a total of 46 (7.7%) patients reported cases of skin reaction at the site of transdermal system application. The majority of these cases were mild and resolved spontaneously. Overall, therapy was discontinued by 13 (2.2%) patients due to system application site reaction, 8 (2.3%) of those receiving both placebo and Alora and 5 (2.0%) of those receiving only placebo systems.

The following additional adverse reactions have been reported with estrogen therapy (see regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, cardiovascular disease, elevated blood pressure, and hypercalcemia).

1. Genitourinary System. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting. Increase in size of uterine leiomyomata; vaginal candidiasis; change in amount of cervical secretion.
2. Breasts. Tenderness, enlargement.
3. Gastrointestinal. Nausea, vomiting, abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease.
4. Skin. Chloasma or melasma that may persist when the drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism.
5. Eyes. Steepening of corneal curvature; intolerance to contact lenses.
6. Central Nervous System. Headache, migraine, dizziness, mental depression, chorea.
7. Miscellaneous. Increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, edema, changes in libido.

OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of estrogen containing oral contraceptives 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. In either case, the original treatment schedule should be maintained.

Initiation of Therapy

Three Alora strengths having nominal estradiol in vivo delivery rates of 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day (differentiated by the physical size of Alora ) are available for treatment of moderate-to-severe vasomotor symptoms, vulval 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 dose should be adjusted as necessary and the lowest dose required to control symptoms should be used. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.

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.

Therapeutic Regimen

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).

HOW SUPPLIED

Alora 0.05 mg/day (estradiol transdermal system). Each 18 cm ² 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

NDC 52544-471-23    Patient Calendar Box of 24 Systems

Alora 0.075 mg/day (estradiol transdermal system). Each 27 cm ² 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 0.1 mg/day (estradiol transdermal system). Each 36 cm ² system contains 3.0 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 15°-30°C (59°-86°F).

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.

Distributed by: Watson Pharma, Inc.

a subsidiary of Watson Laboratories, Inc.

Corona, CA 92880

REVISED AUGUST 1999

1. Registered trademark of Ciba-Geigy.

PATIENT PACKAGE INSERT

Getting the Best Results with Alora--This Leaflet Can Help

This leaflet describes the correct way to apply and use the Alora patch--the key to getting the best results with Alora . It also talks about the risks and side effects of estrogen use. If you want to know more after you read it, ask your doctor, pharmacist, or other health care professional.

The Alora estradiol transdermal system is a thin, clear, plastic patch that sticks to the skin. Each patch is sealed in a pouch, which protects it until you're ready to put it on. Don't open a pouch or remove a patch until just before you apply it.

What You Need to Do: Checklist

|/  Put on a new patch twice a week. Use one of the schedules on the inside flap of the patch box.

For instance, if you apply your first patch on Sunday, take that patch off on Wednesday and put on a new one. Stick with this schedule as long as you use Alora . To help remind you, mark the schedule on the inside flap of the patch box. Put a check next to the first day you apply the patch.

|/  Place the patch on the lower abdomen (below the panty line) when you first start using Alora.

As you gain more experience applying Alora , you may want to try the hips or buttocks to see which area works best for you.

Do not apply Alora to your breasts or any other parts of the body.

To help the batch stay in place:

• Try not to disturb the patch while putting on and removing clothes. It may help to place the patch where your underwear will cover it at all times.
• Be careful while changing clothes, washing or drying off, so that you do not catch the patch with your clothes or the towel.
• Try different sites on the lower abdomen, hips, or buttocks area to see what works well with your body and your clothing.
• When you first start using the patch, be conscious of it.
• If the patch starts to lift, simply press it back in place.

When you change your patch, don't put the new one in the same place. For instance, if you had Alora on one side of the abdomen, put the new patch on the other side. Wait at least one week before you reuse any spot to help reduce the chance of skin redness or irritation.

|/  Apply the patch with care. Before you begin, read all the information in these four steps.

Step 1. Choose a spot for the patch.

Make sure the skin at the spot is:

• Freshly washed, but dry and cool (wait a few minutes after taking a hot bath or shower).
• Free of body powder or lotion.
• Free of cuts, rashes, or any other skin problem.

Step 2. Open the pouch that contains the patch.

• Locate the notch on the top left or right corner of the pouch.
• Grasp the pouch at the notch and tear off the top edge. Do not cut the pouch with scissors, which might damage the patch inside.
• Pull the patch out.

Step 3. Apply one half of the patch to your skin.

• Remove half of the liner, which covers the sticky surface of the patch. To find the liner, bend the patch in half. Then grab the clear straight edge of the liner and pull that piece off.
• Without touching the sticky surface, press the sticky half of the patch onto your skin. (If you touch the sticky surface, the patch may not stay on as well.)
• Rub the sticky half firmly to ensure full contact with your skin.

Step 4. Apply the second half of the patch to your skin.

• Bend the patch back over itself. Press down on the liner firmly.
• Push the liner forward a little to loosen the edge.

• Grab the loose edge at either corner and peel off the second piece of the liner. Try not to touch the sticky surface of the patch.
• Press the entire patch firmly onto the skin with your finger tips. 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.

|/   Take off the old patch. Fold it in half (sticky sides together) and throw it away out of the reach of children and pets.

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 doctor.

Questions You May Have

Q. Should I take the patch off when I swim or bathe?

A. No. Wear each patch all the time until you put on a new one. Baths, showers, or swimming should not affect the Alora patch as long as you don't rub the patch as you wash. Avoid soaking in a hot tub for a long time, though, which can make the patch come off.

Wearing the patch while spending time in the sun should be no problem. Just be sure you put the patch on a spot your clothing or bathing suit covers.

Q. What should I do if the patch comes off?

A. If the patch starts to lift off your skin, apply a little pressure with your fingertips. The patch is designed to restick. Most women find that the Alora patch seldom comes off. But if it does, try putting the same patch back on the same spot. If it sticks firmly all over, leave it on. If not, take it off and put a new patch on a new spot. No matter what day this happens, stick to the twice-a-week schedule that you have marked on the patch box for the next patch.

Q. What should I do if I forget to change the patch on the day it's due?

A. Remove the old patch and apply a new one to a new spot as soon as you remember. No matter what day this happens, stick to your twice-a-week schedule for the next patch.

Q. How long should I keep using Alora?

A. The answer will be different for each woman. Talk to your doctor every 6 months about how you are feeling and whether you still need estrogen.

For Best Results, Stick with Your Patch Program

• Replace your patch twice each week, on the two days you have chosen. Until it becomes a habit, try:
  
  • Marking your schedule on the inside flap of the patch box;
  • Marking the days on your calendar;
    
  • Linking the days you change your patch to other things that always happen on those days (e.g., an exercise class, meetings, etc.)
• Handle each patch with care.
  
  • Make sure the skin is clean, dry, and free of lotion and powder.
  • Try to avoid touching the sticky surface when applying the patch.
  • Be careful while changing clothes, washing or drying off, so that you do not catch the patch with your clothes or the towel.
  • When you first start using the patch, be conscious of it.
  • If the patch starts to lift, simply press it back in place.
• Keep working with your doctor, pharmacist, or other health care professional. Ask questions. If you have concerns, talk them over--don't just stop using the patch on your own. Remember, it may take a little time and some experience to get accustomed to using a patch.
• Get your refills of the Alora patch before your supply runs out.

If you would like more information on the Alora patch, please call toll free 1-888-ALORA-4-U (1-888-256-7248).

INFORMATION FOR THE PATIENT

INTRODUCTION

This leaflet describes when and how to use estrogens, and the risks and benefits of estrogen treatment. Your doctor has prescribed the Alora estradiol transdermal system for the treatment of your menopausal symptoms. Estradiol is the same hormone that your ovaries produce abundantly before menopause. During menopause, production of estrogen hormones by your body decreases well below the amounts normally produced during your fertile years. In many women this decrease in estrogen production causes uncomfortable symptoms, most noticeably hot flashes and sleep disturbances. Estrogens can be given to reduce or eliminate these symptoms.

Estrogens have important benefits but also some risks. You must decide, with your doctor, whether the benefits of estrogen use outweigh the risks. If you use estrogens, check with your doctor to be sure you are using the lowest possible dose that works and that you don't use them longer than necessary. How long you need to use estrogens will depend on the reason for use.

INFORMATION ABOUT ALORA

How Alora Works

The Alora estradiol transdermal system that your doctor has prescribed for you releases small amounts of estradiol through the skin and into the blood stream in a continous way. The dose of estradiol you require will depend on your individual response. The dose is adjusted by the size of the Alora estradiol transdermal system. Alora is available in three sizes.

Benefits of Treatment with Alora

Regular twice weekly use of Alora offers relief from moderate-to-severe symptoms of menopause, hot flashes and vaginal dryness. Small quantities of the naturally occurring hormone estradiol are absorbed through the skin from the Alora estradiol transdermal system, ensuring a continuous supply of circulating hormone in the body.

When estradiol is administered through the skin, the hormone does not undergo the rapid chemical changes in the liver and stomach that would occur if you were taking it in tablet or capsule form by mouth.

USES OF ESTROGEN

(Not every estrogen drug is approved for every use listed in this section. If you want to know which of these possible uses are approved for the medicine prescribed for you, ask your doctor or pharmacist to show you the professional labeling. You can also look up the specific estrogen product in a book called the "Physician' Desk Reference", which is available in many book stores and public libraries. Generic drugs carry virtually the same labeling information as their brand name versions.)

• To reduce moderate or severe menopausal symptoms.
  Estrogens are hormones made by the ovaries of women. Between ages 45 and 55, the ovaries normally stop making estrogens. This drop in body estrogen levels causes the "change of life" or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place and the sudden drop in estrogen levels causes "surgical menopause."
  When estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating ("hot flashes" or "hot flushes"). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms. Some women have only mild menopausal symptoms, or none at all, and do not need estrogen therapy for these symptoms. Other women may need estrogens for a few months while their bodies adjust to lower estrogen levels. For the treatment of menopausal symptoms, the majority of women need estrogen replacement therapy for no longer than 6 months. Since every woman is different, you and your doctor should periodically reevaluate your need for continued estrogen use.
• To treat vulval and vaginal atrophy (itching, burning, dryness in or around the vagina, difficulty or burning on urination) associated with menopause.
• To treat certain conditions in which a young woman's ovaries do not produce enough estrogen naturally.
• To treat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding.
• To treat certain cancers in special situations, in men and women.
• To prevent thinning of bones.
  Osteoporosis is a thinning of the bones that makes them weaker and allows them to break more easily. The bones of the spine, wrists, and hips break most often in osteporosis. Both men and women start to lose bone mass after about age 40, but women lose bone mass faster after menopause. Using estrogens after menopause slows down bone thinning and may prevent bones from breaking. Lifelong adequate calcium intake, either in the diet (such as dairy products) or by calcium supplements (to reach a total daily intake of 1000 milligrams before menopause or 1500 milligrams after menopause) may help to prevent osteoporosis. Regular weight-bearing exercise (like walking or running for an hour, two or three times a week) may also help to prevent osteoporosis. Before you change your calcium intake or exercise habits, it is important to discuss these lifestyle changes with your doctor to find out if they are safe for you.
  Since estrogen use has some risks, only women who are likely to develop osteoporosis should use estrogens to prevent this condition. Women who are likely to develop osteoporosis often have the following characteristics: white or Asian race, slim, cigarette smokers, and a family history of osteoporosis in a mother, sister, or aunt. Women who have relatively early menopause, often because their ovaries were surgically removed, are more likely to develop osteoporosis than women whose menopause happens at the average age (about 45 to 55 years).

WHO SHOULD NOT USE ESTROGENS

Estrogens shoult not be used:

• During pregnancy (see boxed Warning ).
  If you think you may be pregnant, do not use any form of estrogen-containing drug. Using estrogens while you are pregnant may cause your unborn child to have birth defects. Estrogens do not prevent miscarriage.
• If you have unusual vaginal bleeding which has not been evaluated by your doctor (see boxed Warning ).
  Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus.
• If you have had cancer.
  Since estrogens increase the risk of certain types of cancer, you should not use estrogens if you have ever had cancer of the breast or uterus, unless your doctor recommends that the drug may help in the cancer treatment. (For certain patients with breast or prostate cancer, estrogens may help.)
• If you have any circulation problems.
  Estrogen therapy should not be used except in unusually special situations and only after consultation with your doctor and only in recommended doses. Patients with a tendency for abnormal blood clotting should avoid estrogen use (see DANGERS OF ESTROGENS , below).
• When they do not work.
  During menopause, some women develop nervous symptoms or depression. Estrogens do not relieve these symptoms. You may have heard that taking estrogens for years afer menopause will keep your skin soft and supple and keep you feeling young. There is no evidence for these claims and such long-term estrogen use may have serious risks.
• After childbirth or when breast-feeding a baby.
  Estrogens should not be used to try to stop the breasts from filling with milk after a baby is born. Such treatment may increase the risk of developing blood clots (see DANGERS OF ESTROGENS , below).
  If you are breast-feeding, you should avoid using any drugs because many drugs pass through to the baby in the milk. While nursing a baby, you should take drugs only on the advice of your health care provider.

DANGERS OF ESTROGENS

• Cancer of the uterus.
  The risk of developing cancer of the uterus gets higher the longer estrogens are used and when larger doses are taken. One study showed that when estrogens are discontinued, this increased risk of cancer seems to fall off quickly. Three other studies showed that the risk for uterine cancer stayed high for 8 to more than 15 years after stopping estrogen treatment. Because of this risk, IT IS IMPORTANT TO TAKE THE LOWEST DOSE THAT WORKS AND TO TAKE IT ONLY AS LONG AS YOU NEED IT.
  Using progestin therapy together with estrogen therapy may reduce the higher risk of uterine cancer related to estrogen use (see OTHER INFORMATION , below.)
  If you have had your uterus removed (total hysterectomy), there is no danger of developing cancer of the uterus.
• Cancer of the breast.
  Most studies have shown no association between the usual doses used for estrogen replacement therapy and breast cancer. However, some studies have reported that breast cancer developed more often (up to twice the usual rate) in women who used estrogens for long periods of time (especially longer than 10 years), or who used higher doses for shorter periods of time.
  Regular breast examinations by a health professional and monthly self-examination are recommended for women receiving estrogen therapy, as they are for all women.
• Gallbladder disease.
  Women who use esrogens after menopause are more likely to develop gallbladder disease needing surgery than women who do not use estrogens.
• Abnormal blood clotting.
  Taking estrogens may increase the risk of blood clots. These changes allow the blood to clot more easily, possibly allowing clots to form in your bloodstream. If blood clots do form in your bloodstream, they can cut off the blood supply to vital organs, causing serious problems. These clots can cause a stroke (by cutting off blood to the brain), heart attack (by cutting off blood to the heart), a pulmonary embolus (by cutting off blood to the lungs), or other problems. Any of these conditions may be fatal or cause serious long-term disability. However, most studies of low-dose estrogen usage by women do not show an increased risk of these complications.

SIDE EFFECTS

In addition to the risks listed above, the following side effects have been reported with estrogen use:

• Nausea and vomiting.
• Breast tenderness or enlargement.
• Enlargement benign tumors ("fibroids") of the uterus.
• Retention of excess fluid. This may make some conditions worsen, such as asthma, epilepsy, migraine, heart disease, or kidney disease.
• A spotty darkening of the skin, particularly on the face.
• Skin irritation, redness, or rash may occur at the site of application.

REDUCING RISK OF ESTROGEN USE

If you use estrogens, you can reduce your risks by doing these things:

• See your doctor regularly.
  While you are using estrogens, it is important to visit your doctor at least once a year for a check-up. If you develop vaginal bleeding while taking estrogens, you may need further evaluation. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have more frequent breast examinations.
• Reassess your need for estrogens.
  You and your doctor should reevaluate whether or not you still need estrogens at least every six months.
• Be alert for signs of trouble.
  If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately:
  
  • Abnormal bleeding from the vagina (possible uterine cancer).
  • Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clots in the legs, heart or lungs).
  • Severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye).
  • Breast lumps (possible breast cancer; ask your doctor or health professional to show you how to examine your breasts monthly).
  • Yellowing of the skin or eyes (possible liver problem).
  • Pain, swelling or tenderness in the abdomen (possible gallbladder problem).

OTHER INFORMATION

1. Estrogens increase the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus. If your uterus has not been removed, your doctor may choose to prescribe a progestin, a different hormone drug to be used in association with estrogen treatment. Progestin lowers the risk of developing endometrial hyperplasia, a possible precancerous condition of the uterine lining, which may occur while using estrogen.
   There may be additional risks associated with the use of progestin together with estrogen treatment. The possible risks include:
   
   • unfavorable effects on blood fats (especially the lowering of HDL blood cholesterol, the "good" cholesterol which protects against heart disease);
   • unhealthy effects on blood sugar (which might make a diabetic condition worse); and
   • a possible further increase in breast cancer risk which may be associated with long-term estrogen use.
     Some research has suggested that estrogen taken without progestin may protect women against developing heart disease. However, this effect of estrogen is not certain because the estrogen-treated women had characteristics known to protect against heart disease; they were slimmer, more physicaly active, and less likely to have diabetes.
     You are cautioned to discuss very carefully with your doctor or healthcare provider all the possible risks and benefits of long-term estrogen and progestin treatment, as they affect you personally.
2. Your doctor has prescribed this drug for you and you alone. Do not give the drug to anyone else.
3. If you will be taking calcium supplements as part of the treatment to help prevent osteoporosis, check with your doctor about how much to take.
4. Keep this and all drugs out of the reach of children. In case of overdose, remove the system and call your doctor, hospital, or poison control center immediately. Dispose of used Alora estradiol transdermal systems in a manner that prevents accidental application or ingestion by children, pets, or others.

This leaflet provides a summary of the most important information about estrogens. If you want more information, ask your doctor or pharmacist to show you the professional labeling.

HOW SUPPLIED

Alora estradiol transdermal system 0.05 mg/day

Patient Calendar Box of 8 Systems ( NDC 52544-471-08)

Patient Calendar Box of 24 Systems ( NDC 52544-471-23)

Alora estradiol transdermal system 0.075 mg/day

Patient Calendar Box of 8 Systems ( NDC 52544-472-08)

Alora estradiol transdermal system 0.1 mg/day

Patient Calendar Box of 8 Systems ( NDC 52544-473-08)

Store at 15°-30°C (59°-86°F).

Do not store unpouched.

Apply immediately upon removal from the protective pouch.

Distributed by: Watson Pharma, Inc.

a subsidiary of Watson Laboratories, Inc.

Corona, CA 92880

REVISED AUGUST 1999

U.S. Patent Nos. 5,122,383; 5,227,168; 5,212,199; and 5,164,190