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.
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 .
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.
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.
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.
Alora has been studied only in postmenopausal women.
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:
Estrogens should not be used in individuals with any of the following conditions:
See Patient Package Insert printed below.
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.
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 ).
Estrogens should not be used during pregnancy (see CONTRAINDICATIONS and Boxed ).
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.
The safety and effectiveness in geriatric patients (over age 65) have not been established.
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.
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.
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).
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.
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.
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.
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).
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.
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.
|/ 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.
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:
Step 2. Open the pouch that contains the patch.
Step 3. Apply one half of the patch to your skin.
Step 4. Apply the second half of the patch to your skin.
|/ 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.
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.
If you would like more information on the Alora patch, please call toll free 1-888-ALORA-4-U (1-888-256-7248).
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.
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.
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.
(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.)
Estrogens shoult not be used:
In addition to the risks listed above, the following side effects have been reported with estrogen use:
If you use estrogens, you can reduce your risks by doing these things:
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.
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