Alora

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy.

Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process, the rate of diffusion across the stratum corneum being the principal factor. Alora presents sufficient concentration of estradiol to the surface of the skin to maintain continuous transport over the 3 to 4 day dosing interval.

Direct measurement of total absorbed dose of estradiol through analysis of residual estradiol content of systems worn over a continuous 4-day interval during 251 separate occasions in 123 postmenopausal women demonstrated that the average daily dose absorbed from Alora was 0.003 ± 0.001 mg estradiol per cm² active surface area. The nominal mean in vivo daily delivery rates of estradiol calculated from these data are 0.027 mg/day, 0.054 mg/day, 0.081 mg/day, and 0.11 mg/day for the 9 cm², 18 cm², 27 cm², and 36 cm² Alora, respectively.

In another study, 20 women also were treated with three consecutive doses of Alora 0.05 mg/day, Alora 0.075 mg/day and Alora 0.1 mg/day on abdominal application sites. Mean steady-state estradiol serum concentrations observed over the dosing interval are shown in Figure 1.

Figure 1: Mean steady-state estradiol serum concentration during the third twice weekly dose of Alora 0.1 mg/day, Alora 0.075 mg/day, and Alora 0.05 mg/day in 20 postmenopausal women.

In a single dose randomized crossover study conducted to compare the effect of site of Alora application, 31 postmenopausal women wore single Alora 0.05 mg/day for 4-day periods on the lower abdomen, upper quadrant of the buttocks, and outside aspect of the hip. The estradiol serum concentration profiles are shown in Figure 2.

Figure 2: Mean estradiol serum concentrations during a single 4-day wearing of Alora 0.05 mg/day applied by 31 postmenopausal women to the lower abdomen, upper quadrant of the buttocks or outer aspect of the hip.

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

Table 1 : Mean (SD) Pharmacokinetic Profile of Alora Over an 84-hour Dosing Interval.

Steady-state estradiol serum concentrations were measured in two well-controlled clinical trials in the treatment of menopausal symptoms of 3 month duration (Studies 1 and 2), and one trial in the prevention of postmenopausal osteoporosis of 2 year duration (Study 3). Table 2 provides a summary of these data.

Table 2: Mean (SD) steady-state estradiol serum concentrations (pg/ml) in clinical trials of 3 month (Studies 1 and 2) and 2 year (Study 3) duration.

In a 2-year, randomized, double-blind, placebo-controlled, prevention of postmenopausal osteoporosis study in 355 hysterectomized women, the average baseline-adjusted steady-state estradiol serum concentrations were 18.6 pg/ml (45 patients) for the 0.025 mg/day dose, 35.9 pg/ml (47 patients) for the 0.05 mg/day dose, and 50.1 pg/ml (46 patients) for the 0.075 mg/day dose. These values were linearly related and dose proportional.

No specific investigation of the tissue distribution of estradiol absorbed from Alora in humans has been conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent mean (SD) serum half-life of estradiol determined from biopharmaceutic studies conducted with Alora is 1.75 ± 2.87 hours.

Special Populations

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.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, 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.

Clinical Studies

Efficacy of Alora has been studied in a double blind/double dummy, randomized, parallel group, placebo-controlled trial involving a total of 268 postmenopausal women over a 12-week dosing period. Only women having estradiol and FSH serum concentrations in the postmenopausal range and who exhibited a weekly average of at least 60 moderate to severe hot flushes during the screening period were enrolled in the studies.

Patients received Alora 0.05 mg/day and a placebo system, or Alora 0.1 mg/day and a placebo system, or two placebo systems dosed twice weekly over a 12-week duration. Measures of efficacy included mean reduction in weekly number of moderate to severe vasomotor symptoms when compared to the mean baseline average determined during a 2-week predosing screening period. Alora was shown to be statistically better than placebo at Weeks 4 and 12 for relief of both the frequency (see Table 3) and severity of vasomotor symptoms.

Table 3 : Mean Change from Baseline in Frequency of Moderate to Severe Vasomotor Symptoms for Alora Compared to Placebo (ITT).

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.

Lumbar spine bone mineral density (BMD) was measured by DEXA in a 2-year, randomized, multi-center, doubleblind, placebo-controlled study in 355 hysterectomized, nonosteoporotic women (i.e., T-scores > -2.5). Eighty-six percent of the women were Caucasian, the mean age was 53.2 years (range 26 to 69), and the average number of years since menopause (natural or surgical) was not determined. Three Alora doses (0.025 mg/day, 0.05 mg/day, and 0.075 mg/day) were compared to placebo in terms of the % change in BMD from baseline to Year 2. The systems were applied every 3 or 4 days on alternate sides of the lower abdomen. All patients received 1000 mg of oral elemental calcium daily. The average baseline lumbar spine T-score was -0.64 (range -2.7 to 3.8). The % changes in BMD from baseline are illustrated in Figure 3.

Figure 3: Mean % change in BMD from baseline at 1 and 2 years after initiation of therapy with Placebo and Alora 0.025, 0.05, and 0.075 mg/day in the completer and intent-to-treat population with last observation carried forward (LOCF).

A total of 196 patients (44 - 0.025 mg/d, 49 - 0.05 mg/d, 45 - 0.075 mg/d, and 58 - placebo) were included in the completer population compared with 258 patients (59 - 0.025 mg/d, 64 - 0.05 mg/d, 63 - 0.075 mg/d, and 72 - placebo) in the intent-to-treat, last observation carried forward population.

All Alora doses were statistically superior to placebo for the primary endpoint, percent change in BMD from baseline. The mean 2-year (LOCF) percent changes in BMD for 0.025 mg/d, 0.05 mg/d, 0.075 mg/d, and placebo were 1.45%, 3.39%, 4.24%, and - 0.80% respectively.

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) [nonfatal myocardial infarction and CHD death], with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 4 below:

Table 4: Relative and Absolute Risk Seen in the CE/MPA Substudy of WHIa.

For those outcomes included in the “global index,” absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 womenyears. There was no difference between the groups in terms of all-cause mortality [see BOXED WARNINGS and WARNINGS and PRECAUTIONS].

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].

Grapefruit and grapefruit juice may interact with Alora and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

You should not use estradiol if you have: liver disease, a bleeding disorder, unusual vaginal bleeding, history of a hormone-dependent cancer (such as breast, uterine, ovarian, or thyroid cancer), or if you have ever had a heart attack, stroke, or a blood clot.

Do not use if you are pregnant.

Estradiol may increase your risk of developing a condition that may lead to uterine cancer. Your doctor may prescribe a progestin to help lower this risk. Report any unusual vaginal bleeding right away.

Estradiol should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions. Long-term use may also increase your risk of breast cancer or blood clot.

Your doctor should check your progress on a regular basis to determine whether you should continue this treatment.

Other drugs may interact with estradiol, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of this medicine before puberty is not recommended. Growth of bones can be stopped early. Girls and boys may develop growth of breasts. Girls may have vaginal changes, including vaginal bleeding.

This medicine may be used to start puberty in teenagers with some types of delayed puberty.

Geriatric

Elderly people are especially sensitive to the effects of estrogens. This may increase the chance of side effects during treatment, especially stroke, invasive breast cancer, and memory problems.

Pregnancy

Estrogens are not recommended for use during pregnancy or right after giving birth. Becoming pregnant or maintaining a pregnancy is not likely to occur around the time of menopause.

Certain estrogens have been shown to cause serious birth defects in humans and animals. Some daughters of women who took diethylstilbestrol (DES) during pregnancy have developed reproductive (genital) tract problems and, rarely, cancer of the vagina or cervix (opening to the uterus) when they reached childbearing age. Some sons of women who took DES during pregnancy have developed urinary-genital tract problems.

Breast Feeding

Use of this medicine is not recommended in nursing mothers. Estrogens pass into the breast milk and their possible effect on the baby is not known.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Dasabuvir
• Ombitasvir
• Paritaprevir
• Ritonavir
• Tranexamic Acid

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anagrelide
• Aprepitant
• Boceprevir
• Bosentan
• Bupropion
• Carbamazepine
• Ceritinib
• Conivaptan
• Dabrafenib
• Darunavir
• Dasabuvir
• Dexamethasone
• Donepezil
• Eliglustat
• Enzalutamide
• Fosphenytoin
• Griseofulvin
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mitotane
• Modafinil
• Netupitant
• Oxcarbazepine
• Paclitaxel
• Paclitaxel Protein-Bound
• Phenytoin
• Piperaquine
• Pitolisant
• Pixantrone
• Prednisone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Tizanidine
• Topiramate
• Valproic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

For all patients

• Asthma or
• Calcium, too much or too little in blood or
• Diabetes or
• Epilepsy or seizures or
• Heart problems or
• Kidney problems or
• Liver tumors, benign or
• Lupus erythematosus, systemic or
• Migraine headaches—Estrogens may worsen these conditions.

• Blood clotting problems, or history of during previous estrogen therapy—Estrogens usually are not used until blood clotting problems stop; using estrogens is not a problem for most patients without a history of blood clotting problems due to estrogen use.

• Breast cancer or
• Bone cancer or
• Cancer of the uterus or
• Fibroid tumors of the uterus—Estrogens may interfere with the treatment of breast or bone cancer or worsen cancer of the uterus when these conditions are present.

• Bulging eyes or
• Double vision or
• Migraine headache or
• Vision changes, sudden onset including or
• Vision loss, partial or complete—Estrogens may cause these problems. Tell your doctor if you have had any of these problems, especially while taking estrogen or oral contraceptives (“birth control pills”).

• Changes in genital or vaginal bleeding of unknown causes—Use of estrogens may delay diagnosis or worsen condition. The reason for the bleeding should be determined before estrogens are used.

• Endometriosis or
• Gallbladder disease or gallstones, or history of or
• High cholesterol or triglycerides, or history of or
• Liver disease, or history of or
• Pancreatitis (inflammation of pancreas) or
• Porphyria—Estrogens may worsen these conditions. Although estrogens can improve blood cholesterol, they can worsen blood triglycerides for some people.

• Hypothyroid (too little thyroid hormone)—Dose of thyroid medicine may need to be increased.

For males treated for breast or prostate cancer:

• Blood clots or
• Heart or circulation disease or
• Stroke—Males with these medical problems may be more likely to have clotting problems while taking estrogens; the high doses of estrogens used to treat male breast or prostate cancer have been shown to increase the chances of heart attack, phlebitis (inflamed veins) caused by a blood clot, or blood clots in the lungs.

It is very important that your doctor check your progress at regular visits to make sure this medicine does not cause unwanted effects. These visits will usually be every year, but some doctors require them more often.

In some patients using estrogens, tenderness, swelling, or bleeding of the gums may occur. Brushing and flossing your teeth carefully and regularly and massaging your gums may help prevent this. See your dentist regularly to have your teeth cleaned. Check with your medical doctor or dentist if you have any questions about how to take care of your teeth and gums, or if you notice any tenderness, swelling, or bleeding of your gums.

Although the incidence is low, the use of estrogens may increase you chance of getting cancer of the breast, ovaries, or uterus (womb). Therefore, it is very important that you regularly check your breasts for any unusual lumps or discharge. Report any problems to your doctor. You should also have a mammogram (x-ray pictures of the breasts) done if your doctor recommends it. Because breast cancer has occurred in men taking estrogens, regular breast self-exams and exams by your doctor for any unusual lumps or discharge should be done.

If your menstrual periods have stopped, they may start again. This effect will continue for as long as the medicine is taken. However, if taking the continuous treatment (0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone once a day), monthly bleeding usually stops within 10 months.

Also, vaginal bleeding between your regular menstrual periods may occur during the first 3 months of use. Do not stop taking your medicine. Check with your doctor if bleeding continues for an unusually long time, if your period has not started within 45 days of your last period, or if you think you are pregnant.

Tell the doctor in charge that you are using this medicine before having any laboratory test because some results may be affected.

Check with your child's doctor right away if your child starts to have the following symptoms: nipple or breast swelling or tenderness in females, or enlargement of the breasts in males. Your child may have been exposed to Evamist® transdermal spray.

Do not allow your pets to lick or touch the arm where Evamist® transdermal spray was applied. Small pets may be sensitive to this medicine. Call your pet's veterinarian if your pet starts to have the following symptoms: nipple or breast enlargement, swelling of the vulva, or any signs of illness.

Alora is indicated in:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.

2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.

4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.
   
   The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and, when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium to remain in neutral calcium balance. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

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.

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) 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.

Keep out of reach of children.

For all medical inquiries contact:
ACTAVIS
Medical Communications
Parsippany, NJ 07054
1-800-272-5525

Distributed By:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Content Updated: November 2013

200178-12

Applies to estradiol: compounding powder, intramuscular solution, oral tablet, transdermal emulsion, transdermal film extended release, transdermal gel, transdermal spray, vaginal ring

Gastrointestinal

Cases of oral pigmentation and ischemic colitis have been reported rarely.[Ref]

Gastrointestinal side effects have included nausea, abdominal cramps, bloating and vomiting. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy. Cholestatic jaundice, pancreatitis, and enlargement of hepatic hemangiomas have been reported. Postmarketing experience with the vaginal ring has included a few cases of bowel obstruction and vaginal ring use. Postmarketing side effects with Vivelle-Dot include nausea, vomiting, abdominal cramps, bloating, cholelithiasis and diarrhea.[Ref]

Oncologic

Oncologic side effects have included reports of an increased risk of endometrial carcinoma in patients with an intact uterus and less persuasively, with an increased risk of breast cancer.[Ref]

A number of studies have suggested that the risk of endometrial carcinoma is removed (or delayed) by the administration of progestins in combination with estrogen therapy.

The increased risk of breast cancer due to use of estrogens is controversial. Several studies have suggested that long-term estrogen therapy may be associated with a slightly increased risk of breast cancer. Meta analysis of 51 studies (epidemiological data) supports a modest risk increase associated with long-term hormone replacement therapy (HRT).

One study of Swedish women has reported that a 10% increase in the relative risk of breast cancer may occur and that the risk is related to increasing duration of estrogen therapy. In that study, women with more than nine years of estrogen use had a 70% greater relative risk of breast cancer than controls. That study, however, examined use of a variety of estrogen preparations of which estradiol was the most frequently prescribed. In addition, women who took progestins did not demonstrate a decreased risk of breast cancer and may even have been at higher risk.

The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens for more than 15 years was not ruled out.

The Case-Control Surveillance Study has reported that there is "no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long duration of use or long latent intervals, but the possibility of a modest increase (less than a doubling) could not be excluded."

Follow-up to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)

A study of middle-aged women in the Puget Sound area concluded that "on the whole, the use of estrogen with progestin HRT [hormone replacement therapy] does not appear to be associated with an increased risk of breast cancer in middle-aged women."

A prospective cohort study (11 years) of 37,105 women by Gapstur et al evaluated the histology of the breast cancer in women who ever used HRT. No association was found between duration of ever HRT use and the incidence of ductal carcinoma in situ or invasive ductal/lobular carcinoma. The duration of ever HRT use was associated with risk of invasive carcinoma with a favorable prognosis (relative risk (RR) = 1.81, 95% confidence interval (CI), 1.07 to 3.07 for HRT use less than or equal to 5 yrs and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5 yrs, p = 0.005). The relative risk of invasive carcinoma with a favorable prognosis for current users (adjusted for age and other risk factors) was 4.42, CI, 2.00 to 9.76 for less than or equal to 5 yrs and 2.63, CI, 1.18 to 5.89 for > 5 yrs). Risk of invasive ductal or lobular carcinoma for current users less than or equal to 5 yrs was RR = 1.38, CI, 1.03 to 1.85.[Ref]

Cardiovascular

The reported effects of estrogens on cardiovascular activity are variable. Alterations in lipid profiles in treated women are thought to be responsible for reducing cardiovascular risks. Data suggest estrogen use may increase blood pressure, particularly in patients receiving high doses, decrease blood pressure, or result in no change. In addition, noncontraceptive use of estrogens in young women (particularly smokers) may substantially increase the risk of nonfatal myocardial infarction. Other studies have concluded that no increased risk of myocardial infarction exists.[Ref]

Cardiovascular side effects have included studies suggesting that unopposed estrogen therapy decreased the risk of coronary heart disease by as much as 35%. Combination therapy with a progestin may have also decreased coronary risk. However, the extent of risk reduction with combination therapy has not been determined. Data are available that suggest combination therapy does not reduce the overall rate of coronary heart disease in postmenopausal women with established coronary disease. Postmarketing side effects with Vivelle-Dot include deep vein thrombosis, pulmonary embolism and thrombophlebitis.[Ref]

Metabolic

Metabolic side effects have included reports of generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels have occurred. Estrogen therapy may have led to increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects.

Metabolic adverse effects such as hypercalcemia have occurred in patients with breast cancer and bone metastases.[Ref]

Endocrine

Endocrine side effects have included increased levels of thyroxin-binding globulin which led to increased total thyroid serum levels and a decreased in resin uptake of T3. Free thyroid hormone levels remained unchanged. Other endocrine effects have included decreased fasting plasma glucose.[Ref]

General

General side effects have included fluid retention and mastodynia. Alterations in libido have occurred. Postmarketing experience with the vaginal ring has included a few cases of toxic shock syndrome. Postmarketing side effects with Vivelle-Dot include decrease in weight, reduced carbohydrate tolerance and edema.[Ref]

Hepatic

Hepatic side effects have included reports of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas, and well-differentiated hepatocellular carcinomas. Aggravation of porphyria has been reported. Postmarketing side effects with Vivelle-Dot include abnormal liver function tests.[Ref]

Many of the reports of hepatic tumors have occurred in women taking long-term oral contraceptives. However, some tumors have been reported in women taking isolated estrogen therapy.[Ref]

Hematologic

Hematologic side effects have included hypercoagulability and an increase in venous thromboembolism.[Ref]

The clinical significance of such hypercoagulability in postmenopausal women taking estrogens has not been determined.[Ref]

Ocular

Ocular side effects have included alterations in corneal curvature and contact lens discomfort. Retinal vascular thrombosis has been reported. Postmarketing side effects with Vivelle-Dot include intolerance to contact lenses.[Ref]

Hypersensitivity

Hypersensitivity side effects have included reports of reactions including anaphylaxis. Some reports have implicated the dyes contained in some conjugated estrogen formulations. Urticaria and angioedema have also been reported.[Ref]

Postmarketing reports concerning a transdermal product (Climara) have included a few cases in which there were a combination of the symptoms of generalized hives or rash with swelling of the throat or eyelid edema.[Ref]

Other

Other side effects have included reports of a possible increase in the risk of "fibrocystic breast disease" by as much as twofold. Postmarketing side effects with Vivelle-Dot include breast enlargement and pain, nipple discharge, fibrocystic breast changes and breast cancer.[Ref]

Psychiatric

Psychiatric side effects have included case reports of rapid mood cycling in patients with severe depression. Postmarketing side effects with Vivelle-Dot include nervousness, affect liability and irritability.[Ref]

Nervous system

Nervous system side effects have included dementia, dizziness, mental depression, headache, nervousness, irritability exacerbation of epilepsy and new onset or exacerbation of migraine headaches. A case of chorea has been reported in association with estrogen therapy.[Ref]

Dermatologic

Dermatologic side effects have included chloasma or melasma, which did not always resolve following discontinuation of estrogen therapy. Scalp hair loss, hirsutism, erythema nodosum, and hemorrhagic eruptions have occurred. Postmarketing side effects with Vivelle-Dot include erythema multiforme, pruritus, purpura and rash.[Ref]

Genitourinary

Genitourinary side effects have included abnormal uterine bleeding and dysmenorrhea. In some cases, this was bleeding related to endometrial carcinoma. In addition, estrogens have increased the size of preexisting uterine leiomyomata. Postmarketing experience with the vaginal ring has included a few cases of ring adherence to the vaginal wall, making removal difficult. Postmarketing side effects with Vivelle-Dot include vaginal hemorrhage, abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, uterine leiomyomata, vaginitis, vaginal discharge, ovarian cancer and endometrial hyperplasia.[Ref]

Musculoskeletal

Musculoskeletal side effects have included arthralgias. Postmarketing side effects with Vivelle-Dot include leg cramps.[Ref]

Some side effects of Alora may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Estrogenic agents have been associated with urogenital abnormalities in offspring that manifest later in life. Vaginal adenosis, squamous cell dysplasia of the uterine cervix and vaginal cancer have developed later in life in female offspring. In male offspring, the risks of urogenital abnormalities and testicular cancer later in life are increased.

Estradiol has been assigned to pregnancy category X by the FDA. There are no controlled data in human pregnancy. Estradiol is contraindicated during pregnancy.