Combipatch.com

estrogens. Transdermally delivered estradiol is metabolized only to a small extent by the skin and bypasses the Effects on Uterine Bleeding or Spotting
INDICATIONS AND USAGE
Impaired Liver Function and Past History of Cholestatic Jaundice
first-pass effect seen with orally administered estrogen products. Therapeutic estradiol serum levels with lower With the Continuous Combined regimen, of the women treated with CombiPatch and who completed the one- In women with an intact uterus, CombiPatch is indicated for the following: Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be circulating levels of estrone and estrone conjugates are achieved with smaller transdermal doses (daily and year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle • Treatment of moderate to severe vasomotor symptoms associated with the menopause.
poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 • Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause.
associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recur- CombiPatch®
Norethindrone: Norethindrone acetate is hydrolyzed to the active moiety, norethindrone, in most tissues including
through 12 was 53% and 39% for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal rence, medication should be discontinued.
skin and blood. Norethindrone is primarily metabolized in the liver; however, transdermal administration signifi- day treatment groups, respectively. Women who experienced bleeding, usually characterized it as light (inten- Hypothyroidism
(estradiol/norethindrone acetate transdermal system)
cantly decreases metabolism because hepatic first-pass effect is avoided.
sity of 1.3 on a scale of 1 to 4) with a duration of four and six days for the CombiPatch 0.05/0.14 mg per day • Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid Excretion
function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T and CombiPatch 0.05/0.25 mg per day treatment groups, respectively.
Estradiol: Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conju-
CONTRAINDICATIONS
and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement gates. Estradiol has a short elimination half-life of approximately two to three hours; therefore, a rapid decline Incidence of Cumulative Amenorrhea* in CombiPatch® Continuous Combined
CombiPatch should not be used in women under any of the following conditions: therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy.
Prescribing Information
in serum levels is observed after the CombiPatch estradiol/norethindrone acetate transdermal system is Transdermal Therapy by Cycle over a One-Year Period (Intent-to-Treat Population)
• Undiagnosed abnormal genital bleeding.
These patients should have their thyroid function monitored in order to maintain their free thyroid hormone removed. Within four to eight hours serum estradiol concentrations return to untreated, postmenopausal • Known, suspected, or history of cancer of the breast.
• Known or suspected estrogen-dependent neoplasia.
Fluid Retention
Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia.
Concentration data from Phase II and III studies indicate that the pharmacokinetics of estradiol did not • Active deep vein thrombosis, pulmonary embolism or history of these conditions.
(See WARNINGS, Cardiovascular Disorders and Dementia.) factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
change over time, suggesting no evidence of the accumulation of estradiol following extended patch wear • Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
Hypocalcemia
The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 • CombiPatch should not be used in patients with known hypersensitivity to its ingredients.
Estrogens should be used with caution in individuals with severe hypocalcemia.
Norethindrone: The elimination half-life of norethindrone is reported to be six to eight hours. Norethindrone
years of age) during five years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with • Known or suspected pregnancy. There is no indication for CombiPatch in pregnancy. There appears to be Ovarian Cancer
serum concentrations diminish rapidly and are less than 50 pg/mL within 48 hours after removal of the medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical little or no increased risk of birth defects in children born to women who have used estrogens and progestins The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After CombiPatch transdermal delivery system.
Studies and WARNINGS, Cardiovascular Disorders and Malignant Neoplasms, Breast Cancer).
from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS).
an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 Concentration data from Phase II and III studies indicate that the pharmacokinetics of norethindrone did The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of (95% confidence interval 0.77–3.24) but was not statistically significant. The absolute risk for CE/MPA versus not change over time, suggesting no evidence of the accumulation of norethindrone following extended patch developing probable dementia in postmenopausal women 65 years of age or older during four years of WARNINGS
placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estro- treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is gen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer.
Special Populations
unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOL- Cardiovascular Disorders
Other epidemiologic studies have not found these associations.
CombiPatch has been studied only in postmenopausal women.
OGY, Clinical Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.) Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events Exacerbation of Endometriosis
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations Drug Interactions
*Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sus- such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous Endometriosis may be exacerbated with administration of estrogen therapy. A few cases of malignant transfor- and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 thromboembolism or VTE). Should any of these occur or be suspected, estrogens/progestins should be dis- mation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen- absence of comparable data, these risks should be assumed to be similar. Because of these risks, estro- (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin gens with or without progestins should be prescribed at the lowest effective doses and for the shortest CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine and Information Regarding Lipid Effects
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholes- duration consistent with treatment goals and risks for the individual woman.
rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic In the CE/MPA substudy of the WHI (n=16,608 predominantly healthy postmenopausal women) hormone ther- terolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obe- Exacerbation of Other Conditions
effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clar- apy lowered the level of low-density lipoprotein (LDL) cholesterol and increased the level of high-density sity, and systemic lupus erythematosus) should be managed appropriately.
Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lipoprotein (HDL), yet an increased risk of coronary heart disease events was observed. Therefore, estrogens Coronary Heart Disease and Stroke
lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these condi- DESCRIPTION
ithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of and progestins should not be used for the prevention of cardiovascular disease. (See BOXED WARNING and In the Women’s Health Initiative (WHI) study, an increase in the number of strokes was observed in women CombiPatch® (estradiol/norethindrone acetate transdermal system) is an adhesive-based matrix transdermal estrogens and may result in side effects.
CLINICAL PHARMACOLOGY, Clinical Studies.) receiving CE alone compared to placebo.
Patient Information
patch designed to release both estradiol and norethindrone acetate (NETA), a progestational agent, continu- Adhesion
The results of clinical trials conducted in a 90% Caucasian population at low risk for cardiovascular disease In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe
ously upon application to intact skin.
Averaging across six clinical trials lasting three months to one year, of 1,287 patients treated, CombiPatch showed that compared to Vivelle (an estrogen-alone treatment), CombiPatch demonstrated significantly greater nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to Two systems are available, providing the following delivery rates of estradiol and norethindrone acetate.
transdermal systems completely adhered to the skin nearly 90% of the time over the 3- to 4-day wear period.
Laboratory Tests
Less than 2% of the patients required reapplication or replacement of systems due to lifting or detachment.
reductions in total cholesterol (TC) concentrations. Mean high density lipoprotein-cholesterol (HDL-C) values, women receiving placebo (37 versus 30 per 10,000 women-years). The increase in risk was observed in year however, decreased after one year of CombiPatch therapy whereas they were noted to increase in Vivelle Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by Only two patients (0.2%) discontinued therapy during clinical trials due to adhesion failure.
Estradiol
Nominal Delivery Rate2 (mg per day)
users. Shifts in mean TC/HDL-C were minimal after one year of therapy in both Vivelle and CombiPatch treat- clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).
Clinical Studies
In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA com- System Size
Estradiol /NETA
ment groups. Decreases in triglycerides were observed in both CombiPatch regimens.
Drug/Laboratory Test Interactions
Effects on Vasomotor Symptoms
pared to women receiving placebo (29 versus 21 per 10,000 women-years). The increase in risk was observed • Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet The following tables summarize lipid parameters from these two clinical trials in 955 postmenopausal after the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In two clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in women (with intact uteri) after one year of therapy. Subjects were treated with (i) a continuous regimen of count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) a controlled postmenopausal women (n=332), CombiPatch was administered for three 28-day cycles in Continuous CombiPatch alone (Continuous Combined regimen), (ii) a sequential CombiPatch regimen consisting of an complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III; decreased clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch transdermal system Study; HERS) treatment with CE/MPA-0.625 mg/ 2.5 mg per day demonstrated no cardiovascular benefit.
regimen, CombiPatch was applied throughout the three cycles, replacing the system twice weekly. In the 2 Based on in vivo/in vitro flux data, delivery of both components per day via skin of average permeability (Continuous Sequential regimen), or (iii) a continuous regimen with an estradiol-only transdermal system During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle® 0.05 mg) was applied twice • Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as meas- (interindividual variation in skin permeability is approximately 20%).
(Vivelle 0.05 mg). The values below represent mean percent change from baseline in patients with data at events in postmenopausal women with established coronary heart disease. There were more CHD events in weekly during the first 14 days of a 28-day cycle; CombiPatch was applied for the remaining 14 days of the the CE/MPA-treated group than in the placebo group in year one, but not during the subsequent years. Two 4 levels (by column or by radioimmunoassay) or T3 levels by radioim- Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day thousand three hundred and twenty-one women from the original HERS trial agreed to participate in an open 3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations estra-1,3,5(10)-triene-3,17β-diol. The molecular weight of estradiol is 272.39 and the molecular formula is and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The Lipid Profile Values, Adjusted Mean Percent Change from Baseline After One Year
are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from base- of Continuous Combined CombiPatch® Transdermal Therapy
• Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone- years overall. Rates of CHD events were comparable among women in the CE/MPA group and in the placebo Norethindrone acetate USP is a white to creamy white, odorless, crystalline powder, chemically described line to endpoint with either the Continuous Combined or Continuous Sequential administration of CombiPatch binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free CombiPatch®
Vivelle®
group in HERS, HERS II, and overall.
as 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular weight of norethindrone acetate is at all doses as compared to placebo (intent-to-treat population). (See tables below.) hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin Continuous Combined
Continuous
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of substrate, alpha-1-antitrypsin, ceruloplasmin).
the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of Adjusted Mean Change in the Number of Hot Flushes and Daily
The structural formulas for estradiol and norethindrone acetate are • Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
Intensity of Hot Flushes per Day in CombiPatch®
Lipid Parameter (%)
Continuous Combined Transdermal Therapy
Venous Thromboembolism (VTE)
In the Women’s Health Initiative (WHI) study, an increase in VTE was observed in women receiving CE com- • Reduced response to metyrapone test.
CombiPatch®
Carcinogenesis, Mutagenesis, Impairment of Fertility
Continuous Combined
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and Long-term continuous administration of estrogen, with and without progestin, in women with and without a pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED Adjusted Mean Change
Represents milligrams of estradiol/NETA delivered daily by each system.
rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years from Baseline1
2 Comparison with estradiol-only patch was significant (p <0.05).
in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See Long-term continuous administration of natural and synthetic estrogens in certain animal species increases 3 Comparison with estradiol-only patch was significant (p <0.001).
CLINICAL PHARMACOLOGY, Clinical Studies.) the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
4 Total number of patients with available data is 121.
If feasible, estrogens should be discontinued at least four to six weeks before surgery of the type Norethindrone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.
5 Total number of patients with available data is 97.
associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
CombiPatch transdermal systems are comprised of three layers. Proceeding from the visible surface toward Pregnancy
Means were adjusted for imbalance among treatment groups and investigators (least squares mean from Malignant Neoplasms
the surface attached to the skin, these layers are (1) a translucent polyolefin film backing, (2) an adhesive layer CombiPatch should not be used during pregnancy. (See CONTRAINDICATIONS.) Lipid Profile Values, Adjusted Mean Percent Change from Baseline After One Year
Breast Cancer
containing estradiol, norethindrone acetate, acrylic adhesive, silicone adhesive, oleyl alcohol, oleic acid NF, Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
of Continuous Sequential CombiPatch® Transdermal Therapy
Nursing Mothers
The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of povidone USP and dipropylene glycol, and (3) a polyester release protective liner, which is attached to the Population represents those patients who had baseline and endpoint observations.
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.
breast cancer. The most important randomized clinical trial providing information about this issue is the adhesive surface and must be removed before the system can be used.
CombiPatch®
Vivelle®
The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 4-6, severe Detectable amounts of estrogens and progestins have been identified in the milk of mothers receiving these Continuous Sequential
Continuous
Women’s Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies).
drugs. Caution should be exercised when CombiPatch is administered to a nursing mother.
The results from observational studies are generally consistent with those of the WHI clinical trial and report Pediatric Use
no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of Total number of patients with available data is 56.
Lipid Parameter (%)
CombiPatch is not indicated for use in children.
Total number of patients with available data is 50.
Geriatric Use
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for Adjusted Mean Change in the Number of Hot Flushes and Daily
a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/prog- an average of four years, 82% (n=3,729) were 65 to 74 while 18% (n=803) were 75 and over. Most women Intensity of Hot Flushes per Day in CombiPatch®
estin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use.
(80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyproges- Continuous Sequential Transdermal Therapy
In the WHI trial and from observational studies, the excess risk increased with duration of use. From observa- The active components of the system are estradiol USP and norethindrone acetate USP. The remaining terone acetate were reported to have a two-fold increase in the risk of developing probable dementia.
tional studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, components of the system are pharmacologically inactive.
CombiPatch®
1 Represents milligrams of estradiol/NETA delivered daily by each system.
Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estro- observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with Continuous Sequential
Comparison with estradiol-only patch was significant (p <0.05).
gens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable estrogen/progestin combination therapy as compared to estrogen-alone therapy.
CLINICAL PHARMACOLOGY
3 Comparison with estradiol-only patch was significant (p <0.001).
dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.) In the CE/MPA substudy, 26% of the women reported prior use of estrogen-alone and/or estrogen/progestin- Endogenous estrogens are largely responsible for the development and maintenance of the female reproduc- 4 Total number of patients with available data is 116.
Adjusted Mean Change
combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative tive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium 5 Total number of patients with available data is 114.
from Baseline1
ADVERSE REACTIONS
risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more 6 Total number of patients with available data is 103.
See BOXED WARNING, WARNINGS and PRECAUTIONS.
41 versus 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen in nor- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the Women’s Health Initiative Studies
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute mally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women Means were adjusted for imbalance among treatment groups and investigators (least squares mean from the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sul- who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the for identifying the adverse events that appear to be related to drug use and for approximating rates.
the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day com- fate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
absolute risk was 40 versus 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
pared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA Population represents those patients who had baseline and endpoint observations.
coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as Table IV. All Treatment Emergent Study Events Regardless of Relationship
receptors have been identified. These vary in proportion from tissue to tissue.
group compared with the placebo group. Metastatic disease was rare with no apparent difference between the The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 4-6, severe the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast Reported at a Frequency of ≥5% with CombiPatch®
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to VASOMOTOR SYMPTOM STUDIES
follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the ele- other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
vated levels of these hormones seen in postmenopausal women.
The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms CombiPatch®
CombiPatch®
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the Pharmacokinetics
Effects on the Endometrium
requiring further evaluation. All women should receive yearly breast examinations by a health care provider increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the Absorption
The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperpla- and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, Estradiol: Estrogens used in hormone therapy are well absorbed through the skin, mucous membranes, and
sia, a possible precursor of endometrial adenocarcinoma. Progestins counter the estrogenic effects by based on patient age, risk factors, and prior mammogram results.
range 50 to 79, 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are gastrointestinal tract. Administration of CombiPatch every three to four days in postmenopausal women decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial Endometrial Cancer
produces average steady-state estradiol serum concentrations of 45 to 50 pg/mL, which are equivalent to the The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of normal ranges observed at the early follicular phase in premenopausal women. These concentrations are Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle endometrial cancer. The reported endometrial cancer risk among users of unopposed estrogen is about 2- to Table III. Relative and Absolute Risk Seen in the CE/MPA Substudy of WHIa
achieved within 12 to 24 hours following CombiPatch application. Minimal fluctuations in serum estradiol reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with 12-fold or greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose.
concentrations are observed following CombiPatch application, indicating consistent hormone delivery over intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the effi- Most studies show no significant increased risk associated with the use of estrogens for less than one year.
cacy of estrogen therapy for its approved indications.
The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for 5 to 10 years In one study, serum concentrations of estradiol were measured in 40 healthy, postmenopausal women CombiPatch was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
throughout three consecutive CombiPatch applications to the abdomen (each dose was applied for three one year of therapy in two Phase II clinical trials. Nine hundred fifty-five (955) postmenopausal women (with Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table I below.
intact uteri) were treated with (i) a continuous regimen of CombiPatch alone (Continuous Combined regimen), measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of Table I. Mean (SD) Serum Estradiol and Estrone Concentrations
transdermal system (Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen (pg/mL) at Steady-State (Uncorrected for Baseline Levels)
dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was signifi- Estradiol
which may be a precursor to endometrial cancer.
cantly less after one year of therapy with either CombiPatch regimen than with the estradiol-only transdermal Dose Estradiol/NETA
Dementia
system. The tables below summarize these results (intent-to-treat populations).
In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 System Size
(mg per day)
Incidence of Endometrial Hyperplasia in a
years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older.
Continuous Combined CombiPatch® Regimen
After an average follow-up of four years, 40 women being treated with CE/MPA (1.8%, n=2,229) and 21 women in the placebo group (0.9%, n=2,303) received diagnoses of probable dementia. The relative risk for CombiPatch®
Vivelle®
Estrone
CE/MPA versus placebo was 2.05 (95% confidence interval 1.21–3.48), and was similar for women with and Continuous Combined
Continuous
without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger post- No. of Patients
menopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.) Norethindrone: Progestins used in hormone therapy are well absorbed through the skin, mucous membranes,
with Biopsies2
Gallbladder Disease
and gastrointestinal tract. Norethindrone steady-state concentrations are attained within 24 hours of application A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving of the CombiPatch transdermal delivery systems. Minimal fluctuations in serum norethindrone concentrations No. (%) of Patients
a Adapted from JAMA, 2002: 288: 321-333.
are observed following CombiPatch treatment, indicating consistent hormone delivery over the application with Hyperplasia
b Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.
Hypercalcemia
interval. Serum concentrations of norethindrone increase linearly with increasing doses of norethindrone c A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metas- Represents milligrams of estradiol/NETA delivered daily by each system.
invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or 2 Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
tases. If hypercalcemia occurs, the drug should be stopped and appropriate measures taken to reduce the In one study, serum concentrations of norethindrone were measured in 40 healthy, postmenopausal women 3 Comparison of continuous combined regimen versus estradiol-only patch was significant (p value <0.001).
throughout three consecutive CombiPatch applications to the abdomen (each dose was applied for three 3.5- 4 This patient had hyperplasia at baseline.
Visual Abnormalities
day periods). The corresponding pharmacokinetic parameters are summarized in Table II below.
* Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
5 One of 39 patients had hyperplasia in an endometrial polyp.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pend- Table II. Mean (SD) Serum Norethindrone Concentrations (pg/mL) at Steady-State
For those outcomes included in the “global index”, absolute excess risks per 10,000 women-years in the ing examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, Incidence of Endometrial Hyperplasia in a
or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently Dose Estradiol/NETA
group treated with CE/MPA were seven more CHD events, eight more strokes, eight more PEs, and eight more Continuous Sequential CombiPatch® Regimen
1Represents milligrams of estradiol/NETA delivered daily by each system.
System Size
(mg per day)
invasive breast cancers, while absolute risk reductions per 10,000 women-years were six fewer colorectal can- CombiPatch®
Vivelle®
cers and five fewer hip fractures. The absolute excess risk of events included in the “global index” was Continuous Sequential
Continuous
19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality (see PRECAUTIONS
Table V. All Treatment Emergent Study Events Regardless of Relationship
BOXED WARNING, WARNINGS, and PRECAUTIONS.) Reported at a Frequency of ≥5% with CombiPatch®
Women’s Health Initiative Memory Study
Addition of a Progestin When a Woman Has Not Had a Hysterectomy
ENDOMETRIAL HYPERPLASIA STUDIES
Distribution
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with No. of Patients
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly Estradiol: The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would CombiPatch®
CombiPatch®
Vivelle®
with Biopsies2
healthy postmenopausal women 65 years of age and older (47% were aged 65 to 69 years, 35% were 70 to widely distributed in the body and are generally found in higher concentrations in the sex hormone target 74 years, and 18% were 75 years of age and older) to evaluate the effects of oral CE/MPA (0.625 mg conju- be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
No. (%) of Patients
gated equine estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia There are, however, possible risks that may be associated with the use of progestins with estrogens com- Norethindrone: In plasma, norethindrone is bound approximately 90% to SHBG and albumin.
with Hyperplasia
(primary outcome) compared with placebo.
pared to estrogen-alone regimens. These include a possible increased risk of breast cancer.
Metabolism
After an average follow-up of four years, 40 women in the estrogen/progestin group (45 per 10,000 women- Elevated Blood Pressure
Estradiol: Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
1 Represents milligrams of estradiol/NETA delivered daily by each system.
years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyn- estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to cratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is Comparison of continuous sequential regimen versus estradiol-only patch was significant (p value <0.001).
estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals 4 This patient had hyperplasia at baseline.
placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide 5 This patient had hyperplasia in an endometrial polyp.
these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by Hypertriglyceridemia
reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active plasma triglycerides leading to pancreatitis and other complications.
HOW SUPPLIED
Where do you apply CombiPatch?
This leaflet provides a summary of the most important information about CombiPatch. If you would like CombiPatch® estradiol/norethindrone acetate transdermal delivery system is available in: CombiPatch should be placed on the lower abdomen (below the panty line).
more information, talk with your health care provider or pharmacist. You can ask for information about CombiPatch that is written for health professionals. You can get more information by calling the toll free number Nominal Delivery Rate*
• A smooth (fold-free), clean, dry area of skin.
Estradiol/Norethindrone Acetate
Presentation
Markings
• An area that has been freshly washed and dried well (free of oils, lotions or powders that could keep the patch from sticking well to your skin).
What are the ingredients in CombiPatch?
• An area that has no cuts, rashes, or other skin problems.
CombiPatch transdermal systems are comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyolefin film backing, (2) an adhesive layer Every time you put on a new CombiPatch, move to a different area on your containing estradiol, norethindrone acetate, acrylic adhesive, silicone adhesive, oleyl alcohol, oleic acid NF, Metabolic and Nutritional Disorders lower abdomen than used before. The same area should not be used again povidone USP and dipropylene glycol, and (3) a polyester release protective liner, which is attached to the adhesive surface and must be removed before the system can be used. The active components of the system are estradiol USP and norethindrone acetate USP. The remaining components of the system are pharmacolog- Do not put CombiPatch on or near your breasts. You should not put CombiPatch on the waistline, since
tight clothing may rub off the patch. To avoid disturbing the patch it may help to choose an area where your underwear will cover it all the time.
Where should you store CombiPatch?
How do you apply CombiPatch?
Each CombiPatch is sealed in its own pouch. To protect the medication, store the patch in the pouch until you • Each CombiPatch is sealed in its own protective pouch.Tear open this pouch at the slit (do not use scissors) and remove the patch. The pouch should not Before CombiPatch was sold to you, the pharmacist stored the package in the refrigerator. You can store
*Nominal delivery rate described. See DESCRIPTION for more details regarding drug delivery.
be opened until you are ready to put the patch on.
CombiPatch at room temperature, below 77ºF (25ºC). The patch sticks best to your skin when stored at
Storage Conditions
room temperature. For best results, DO NOT store CombiPatch patches in the refrigerator or in areas where Prior to dispensing to the patient, store refrigerated 2-8° C (36-46° F). After dispensing to the patient, the temperature can become extreme (very high or very low), such as in DIRECT SUNLIGHT or in a car.
CombiPatch can be stored at room temperature below 25° C (77° F) for up to six months. For the Pharmacist:
When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not Keep this and all medicines out of the reach of children.
exceed either six months from the date of sale or the expiration date, whichever comes first.
• A protective liner covers the adhesive side of the patch. Peel off one side Store the systems in the sealed foil pouch.
of the protective liner. Do not touch the sticky part of the patch with your Do not store the system in areas where extreme temperatures can occur.
Keep this and all medicines out of the reach of children.
Vivelle® is a registered trademark of Novartis Pharmaceuticals Corporation.
• Put the sticky side of the patch on an area of skin on your lower abdomen.
Peel off the second side of the protective liner.
PATIENT INFORMATION
1Represents milligrams of estradiol/NETA delivered daily by each system.
CombiPatch®
Noven Pharmaceuticals Inc.
Miami, FL 33186 (estradiol/norethindrone acetate transdermal system)
The following additional adverse reactions have been reported with estrogen and/or progestin therapy.
Genitourinary System
• Press the patch firmly in place with your hand for about 10 seconds.
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; Make sure there is good contact, especially around the edges.
dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
Please read this PATIENT INFORMATION before you start using CombiPatch® (estradiol/norethindrone acetate transdermal system) and read all the information that you get each time you refill CombiPatch. There Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
may be new information. This information does not take the place of talking to your health care provider about Cardiovascular
your medical condition or your treatment.
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke;increase in blood pressure.
WHAT IS THE MOST IMPORTANT INFORMATION YOU SHOULD KNOW ABOUT COMBIPATCH
Gastrointestinal
(A COMBINATION OF ESTROGEN AND PROGESTIN HORMONES)?
Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder dis- When changing CombiPatch, peel off the used patch slowly. Fold the used patch in half (sticky sides ease; pancreatitis, enlargement of hepatic hemangiomas.
• Do not use estrogens and progestins to prevent heart disease, heart attacks, strokes, or dementia.
together) and throw it in the trash. Please remember to keep CombiPatch out of the reach of children.
If any adhesive remains on your skin after removal of the patch, let the area dry for 15 minutes. Then Chloasma or melasma, that may persist when drug is discontinued; erythema multiforme; erythema nodosum; Using estrogens and progestins may increase your chances of getting heart attacks, strokes, breast gently rub the area with an oil-based cream or lotion to remove the adhesive from your skin.
hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
Eyes
cancer, and blood clots. Using estrogens and progestins may increase your risk of dementia. You and Retinal vascular thrombosis, intolerance to contact lenses.
your health care provider should talk regularly about whether you still need treatment with CombiPatch.
What if you forget to put on a new CombiPatch?
Central Nervous System
If you are currently wearing a patch, remove it and put on a new patch in a different area of your lower Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exac- abdomen. Then go back to changing the patch on the same days each week.
What is CombiPatch?
Miscellaneous
CombiPatch is a medicine that contains two kinds of hormones, estrogen and progestin.
Can you wear CombiPatch when bathing, swimming, or in the sun?
Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; • Bathing, swimming, or showering should not affect the patch. Make sure that the patch does not loosen leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; CombiPatch is available in two round sizes: exacerbation of asthma; increased triglycerides.
• The patch should not be exposed to the sun for long periods of time. Once in place, make sure that the Amount of Each Drug
Amount of Each Drug
patch is covered by your clothing (but remember not to apply CombiPatch on or near your breasts).
in Each System
Released Every Day
OVERDOSAGE
Estradiol/NETA (mg)
Estradiol/NETA (mg per day)
Overdosage may cause nausea, and withdrawal bleeding may occur in females. Serious ill effects have not What should you do if CombiPatch comes off?
been reported following acute ingestion of large doses of estrogen/progestin-containing oral contraceptives by Most women find that CombiPatch seldom comes off. But if a patch should fall off, the same patch may be put young children. In the event of a possible overdosage, the system should be removed immediately and med- on a different area of the lower abdomen (make sure you are choosing a clean, dry, lotion-free area of skin). If the patch will not stick completely to your skin, put a new CombiPatch on a different area of the lower What is CombiPatch used for?
abdomen. No matter what day this happens, go back to changing the patch on the same days each week.
DOSAGE AND ADMINISTRATION
When estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be initi- • Reduce moderate to severe hot flashes.
What are the possible side effects of estrogens?
ated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a estrogen alone or in combination with a progestin, should be limited to the shortest duration consistent with Less common but serious side effects include:
woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or CombiPatch®
treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an opera- appropriate (e.g., 3-month to 6-month intervals) to determine whether treatment is still necessary (see BOXED tion before natural menopause takes place. The sudden drop in estrogen levels causes “surgical (estradiol/norethindrone acetate transdermal system)
WARNING 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 When estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as persistent or recurring abnormal vaginal bleeding.
feelings of warmth in the face, neck, and chest or sudden strong feelings of heat and sweating (“hot flashes” Initiation of Therapy
or “hot flushes”). In some women the symptoms are mild, and they will not need estrogens. In other women, Treatment of postmenopausal symptoms is usually initiated during the menopausal stage when vasomotor symptoms can be more severe. You and your health care provider should talk regularly about whether you symptoms occur. Patients should be started at the lowest dose. Estrogens with or without progestins should be still need treatment with CombiPatch.
prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks • Treat moderate to severe dryness, itching and burning in or around the vagina.
for the individual woman. The lowest effective dose of CombiPatch has not been determined in clinical trials.
These are some of the warning signs of serious side effects:
You and your health care provider should talk regularly about whether you still need treatment with Women not currently using continuous estrogen or combination estrogen/progestin therapy may start therapy CombiPatch to control these problems. If you use CombiPatch only to treat your dryness, itching, and burn- with CombiPatch at any time. However, women currently using continuous estrogen or combination ing in and around your vagina, talk with your health care provider about whether a topical vaginal product estrogen/progestin therapy should complete the current cycle of therapy, before initiating CombiPatch therapy.
Women often experience withdrawal bleeding at the completion of the cycle. The first day of this bleeding • Treat certain conditions in which a young woman’s ovaries do not produce enough estrogens
would be an appropriate time to begin CombiPatch therapy.
naturally.
Therapeutic Regimens
Combination estrogen/progestin regimens are indicated for women with an intact uterus. Two CombiPatch (estradiol/NETA) transdermal delivery systems are available: 0.05 mg estradiol with 0.14 mg NETA per day Who should not use CombiPatch?
(9 sq cm) and 0.05 mg estradiol with 0.25 mg NETA per day (16 sq cm). The lowest effective dose should be Do not use CombiPatch if you have had your uterus removed (hysterectomy). CombiPatch contains a
used. For all regimens, women should be reevaluated at 3- to 6-month intervals to determine if changes in hor- progestin to decrease the chances of getting cancer of the uterus. If you do not have a uterus, you do not mone therapy or if continued hormone therapy is appropriate.
need a progestin and you should not take CombiPatch.
Continuous Combined Regimen
Call your health care provider right away if you get any of these warning signs, or any other unusual symptom A CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 sq cm) matrix transdermal system is worn continuously on the lower abdomen. Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 sq cm system) is available • Have unusual vaginal bleeding.
if a greater progestin dose is desired. A new system should be applied twice weekly during a 28-day cycle.
• Currently have or have had certain cancers. Estrogens may increase the chances of getting certain types
Common side effects include:
Irregular bleeding may occur particularly in the first six months, but generally decreases with time, and often to of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your health care provider about whether you should take CombiPatch.
Continuous Sequential Regimen
• Had a stroke or heart attack in the recent past (for example in the past year).
--- Irregular vaginal bleeding or spotting CombiPatch can be applied as a sequential regimen in combination with an estradiol-only transdermal delivery • Currently have or have had blood clots.
CombiPatch®
• Currently have or have had liver problems.
In this treatment regimen, an 0.05 mg per day (nominal delivery rate) estradiol transdermal system (Vivelle) • Are allergic to CombiPatch or any of its ingredients. See the end of this leaflet for a list of ingredients in
(estradiol/norethindrone acetate transdermal system)
is worn for the first 14 days of a 28-day cycle, replacing the system twice weekly according to product directions.
For the remaining 14 days of the 28-day cycle, CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 sq cm) • Think you may be, or know that you are, pregnant.
transdermal system should be applied to the lower abdomen. Additionally, a dose of 0.05 mg estradiol/0.25 mg Other side effects include:
NETA (16 sq cm system) is available if a greater progestin dose is desired. The CombiPatch system should be Tell your health care provider:
replaced twice weekly during this period in the cycle. Women should be advised that monthly withdrawal • If you are breast-feeding. The hormones in CombiPatch can pass into your milk.
• About all of your medical problems. Your health care provider may need to check you more carefully if
Application of the System
you have certain conditions such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, Site Selection
or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
--- Enlargement of benign tumors of the uterus (“fibroids”) CombiPatch should be placed on a smooth (fold-free), clean, dry area of the skin on the lower abdomen.
• About all the medicines you take, including prescription and nonprescription medicines, vitamins, and
CombiPatch should not be applied to or near the breasts. The area selected should not be oily (which can
herbal supplements. Some medicines may affect how CombiPatch works. CombiPatch may also affect how impair adherence of the system), damaged, or irritated. The waistline should be avoided, since tight clothing Other side effects of CombiPatch are possible. For more information, ask your health care provider or may rub the system off or modify drug delivery. The sites of application must be rotated, with an interval of at • If you are going to have surgery or will be on bed rest. You may need to stop taking estrogens.
least one week allowed between applications to the same site.
Application
How should you use CombiPatch?
What can you do to lower your chances of a serious side effect with CombiPatch?
After opening the pouch, remove one side of the protective liner, taking care not to touch the adhesive part of • Start at the lowest dose and talk to your health care provider about how well that dose is working for you.
• Talk with your health care provider regularly about whether you should continue using CombiPatch.
the transdermal delivery system with the fingers. Immediately apply the transdermal delivery system to a • Estrogens and progestins should be used at the lowest dose possible for your treatment, only as long as • See your health care provider right away if you get vaginal bleeding while using CombiPatch.
smooth (fold-free) area of skin on the lower abdomen. Remove the second side of the protective liner and needed. The lowest effective dose of CombiPatch has not been determined in clinical trials. You and your • Have a breast exam and mammogram (breast X-ray) every year unless your health care provider tells you press the system firmly in place with the hand for at least 10 seconds, making sure there is good contact, health care provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking something else. If members of your family have had breast cancer or if you have ever had breast lumps or and whether you still need treatment with CombiPatch.
an abnormal mammogram, you may need to have breast exams more often.
Care should be taken that the system does not become dislodged during bathing and other activities. If a CombiPatch is a thin, opaque, plastic patch that sticks to the skin. Each patch is sealed in a pouch that pro- • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use system should fall off, the same system may be reapplied to another area of the lower abdomen. If necessary, tects it until you are ready to put it on. Do not open the pouch or remove a patch until just before you apply it.
tobacco, you may have higher chances for getting heart disease. Ask your health care provider for ways to a new transdermal system may be applied, in which case, the original treatment schedule should be contin- lower your chances for getting heart disease.
ued. Only one system should be worn at any one time during the 3- to 4-day dosing interval.
How often should you apply CombiPatch?
Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time.
General information about the safe and effective use of CombiPatch
Removal of the System
• Put on a new CombiPatch every 3 to 4 days, according to your health care provider's instructions.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do Removal of the system should be done carefully and slowly to avoid irritation of the skin. Should any adhesive • Wear the patch all the time until it is time to replace it with a new patch.
not use CombiPatch for conditions for which it was not prescribed. Do not give CombiPatch to other people, remain on the skin after removal of the system, allow the area to dry for 15 minutes. Then gently rub the area • Change the patch on the same days each week. Your CombiPatch package contains a calendar checklist
even if they have the same symptoms you have. It may harm them. Keep CombiPatch out of the reach of
with an oil-based cream or lotion to remove the adhesive residue.
to help you remember a schedule. Mark the 2-day schedule you plan to follow.
• Only one CombiPatch should be worn at any one time.
children.
Ready for Press

Source: http://www.combipatch.com/documents/combipatch-prescribing-information.pdf