DailyMed Label: CombiPatch (estradiol/norethindrone acetate transdermal system)

DailyMed Label: CombiPatch (estradiol/norethindrone acetate transdermal system)

2024

DailyMed Prescription

CombiPatch (estradiol/norethindrone acetate transdermal system)

estradiol/norethindrone acetate transdermal system

Noven Therapeutics, LLC

NDC: 68968-0514

NDC: 68968-0525

NDC: 68968-0514

NDC: 68968-0525

NDC: 68968-0514

NDC: 68968-0514

NDC: 68968-0525

NDC: 68968-0525

CombiPatch ® (estradiol/norethindrone acetate transdermal system) is an adhesive-based matrix transdermal patch designed to release both estradiol, an estrogen, and norethindrone acetate (NETA), a progestational agent, continuously upon application to intact skin. Two systems are available, providing the following in vivo delivery rates of estradiol and NETA. 1 NETA=norethindrone acetate. 2 Based on in vivo/in vitro flux data, delivery of both components per day via skin of average permeability (interindividual variation in skin permeability is approximately 20 percent).       System Size Estradiol (mg) NETA 1 (mg) Nominal Delivery Rate 2 (mg per day) Estradiol / NETA       9 cm 2 round 0.62 2.7 0.05/0.14       16 cm 2 round 0.51 4.8 0.05/0.25 Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17 β -diol. The molecular weight of estradiol is 272.39 and the molecular formula is C 18 H 24 O 2 . NETA USP is a white to creamy white, odorless, crystalline powder, chemically described as 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular weight of NETA is 340.47 and the molecular formula is C 22 H 28 O 3 . The structural formulas for estradiol and NETA are: CombiPatch is comprised of 3 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 containing estradiol, NETA, acrylic adhesive, silicone adhesive, oleic acid NF, 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 NETA USP. The remaining components of the system are pharmacologically inactive. Chemical Structure Layer

CombiPatch is indicated in a woman with a uterus for: Treatment of moderate to severe vasomotor symptoms due to menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. A woman without a uterus generally does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin. Use of estrogen-alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine whether treatment is still necessary. Adequate diagnostic measures, such as directed or random endometrial sampling, when indicated, should be undertaken to rule out malignancy in a postmenopausal woman with a uterus with undiagnosed persistent or recurring abnormal genital bleeding. Initiation of Therapy Patients should be started at the lowest dose. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. The lowest effective dose of CombiPatch has not been determined in clinical trials. Women not currently using continuous estrogen or combination estrogen plus progestin therapy may start therapy with CombiPatch at any time. However, women currently using continuous estrogen or combination estrogen plus 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 would be an appropriate time to begin CombiPatch therapy. Therapeutic Regimens Combination estrogen plus 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 (9 cm 2 ) and 0.05 mg estradiol with 0.25 mg NETA per day (16 cm 2 ). The lowest effective dose should be used. For all regimens, women should be reevaluated at 3- to 6-month intervals to determine if changes in hormone therapy or if continued hormone therapy is appropriate. Continuous Combined Regimen CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 cm 2 ) matrix transdermal system is used for continuous uninterrupted treatment applied twice weekly on the lower abdomen. A new system should be applied to the skin every 3 to 4 days (twice weekly) during a 28-day cycle. Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm 2 system) is available if a greater progestin dose is desired. Irregular bleeding may occur particularly in the first six months, but generally decreases with time, and often to an amenorrheic state. Continuous Sequential Regimen CombiPatch can be applied as a sequential regimen in combination with an estradiol-only transdermal delivery system. In this treatment regimen, a 0.05 mg per day (nominal delivery rate) estradiol transdermal system (Vivelle-Dot ® ) is worn for the first 14 days of a 28-day cycle, replacing the system every 3 to 4 days (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 cm 2 ) transdermal system should be worn continuously on the lower abdomen. The CombiPatch system should be replaced every 3 to 4 days (twice weekly) during this 14-day period in the 28-day cycle. Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm 2 system) is available if a greater progestin dose is desired. Women should be advised that monthly withdrawal bleeding often occurs. Application of the System Site Selection CombiPatch should be placed on a smooth (fold-free), clean, dry area of the skin on the lower abdomen. CombiPatch should not be applied to or near the breasts. The area selected should not be oily (which can impair adherence of the system), damaged, or irritated. The waistline should be avoided, since tight clothing may rub the system off or modify drug delivery. The sites of application must be rotated, with an interval of at least one week allowed between applications to the same site. Application After opening the pouch, remove 1 side of the protective liner, taking care not to touch the adhesive part of the transdermal delivery system with the fingers. Immediately apply the transdermal delivery system to a smooth (fold-free) area of skin on the lower abdomen. Remove the second side of the protective liner and press the system firmly in place with the hand for at least 10 seconds, making sure there is good contact, especially around the edges. Care should be taken that the system does not become dislodged during bathing and other activities. If a system should fall off, the same system may be reapplied to another area of the lower abdomen. If necessary, a new transdermal system may be applied, in which case, the original treatment schedule should be continued. Only 1 system should be worn at any 1 time during the 3- to 4-day dosing interval. Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time. Removal of the System Removal of the system should be done carefully and slowly to avoid irritation of the skin. Should any adhesive remain on the skin after removal of the system, allow the area to dry for 15 minutes. Then gently rub the area with an oil-based cream or lotion to remove the adhesive residue.

CombiPatch is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected, or history of breast cancer. Known or suspected estrogen-dependent neoplasia. Active DVT, PE, or history of these conditions. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions. Known anaphylactic reaction or angioedema or hypersensitivity with CombiPatch. Known liver impairment or disease. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy.

1. Addition of a Progestin when a Woman has not had a Hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. 2. Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. 3. Hypertriglyceridemia In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. 4. Hepatic Impairment and/or Past History of Cholestatic Jaundice Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T 4 and T 3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid Retention Estrogens plus progestins may cause some degree of fluid retention. Women with conditions which might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed. 7. Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. Exacerbation of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Physicians are advised to discuss the content of the PATIENT INFORMATION leaflet and INSTRUCTIONS FOR USE with patients for whom they prescribe CombiPatch. Serum FSH and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure. 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased TBG leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin [CBG], SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma high density lipoprotein (HDL) and HDL-2 subfraction concentrations, reduced low density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 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. NETA was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. CombiPatch should not be used during pregnancy. (See CONTRAINDICATIONS .) There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy. CombiPatch should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens and progestins have been identified in the breast milk of women receiving these drugs. Caution should be exercised when CombiPatch is administered to a nursing woman. CombiPatch is not indicated in children. Clinical studies have not been conducted in the pediatric population. There have not been sufficient numbers of geriatric women involved in studies utilizing CombiPatch to determine whether those over 65 years of age differ from younger subjects in their response to CombiPatch. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES . ) In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age. (See CLINICAL STUDIES . ) The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo. (See CLINICAL STUDIES and WARNINGS , Probable Dementia . ) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS , Probable Dementia . )

See

No drug interaction studies have been conducted with CombiPatch. 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 ( Hypericum perforatum ) preparations, anticonvulsants (e.g., phenobarbital, phenytoin and carbamazepine), phenylbutazone, and anti-infectives (e.g., rifampin, rifabutin, nevirapine and efavirenz) 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 erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, nelfinavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. Adhesion Averaging across 6 clinical trials lasting 3 months to 1 year, of 1,287 patients treated, CombiPatch transdermal systems completely adhered to the skin nearly 90 percent of the time over the 3- to 4-day wear period. Less than 2 percent of the patients required reapplication or replacement of systems due to lifting or detachment. Two patients (0.2 percent) discontinued therapy during clinical trials due to adhesion failure.

CombiPatch estradiol/NETA transdermal delivery system is available in: System Nominal Delivery Rate * Size Estradiol/NETA Presentation NDC Markings 9 cm 2 0.05/0.14 mg per day 8 systems per carton 68968-0514-8 CombiPatch 0.05/0.14 mg per day 16 cm 2 0.05/0.25 mg per day 8 systems per carton 68968-0525-8 CombiPatch 0.05/0.25 mg per day * Nominal delivery rate described. See DESCRIPTION for more details regarding drug delivery. Storage Conditions Store CombiPatch in the refrigerator at 36℉ to 46℉ (2℃ to 8℃). Store the systems in the sealed foil pouch. 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 Corporation. & Vivelle-Dot ® is a registered trademark of Novartis AG.

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 in the 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, 2 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. Absorption Estradiol: Estrogens used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Administration of CombiPatch every 3 to 4 days in postmenopausal women produces average steady-state estradiol serum concentrations of 45 to 50 pg/mL, which are equivalent to the normal ranges observed at the early follicular phase in premenopausal women. These concentrations are achieved within 12 to 24 hours following CombiPatch application. Minimal fluctuations in serum estradiol concentrations are observed following CombiPatch application, indicating consistent hormone delivery over the application interval. In 1 study, serum concentrations of estradiol were measured in 40 healthy, postmenopausal women throughout 3 consecutive CombiPatch applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table 1. Table 1. Mean (SD) Serum Estradiol and Estrone Concentrations (pg/mL) at Steady-State (Uncorrected for Baseline Levels) Estradiol System Size Dose Estradiol/NETA (mg per day) C max C min C avg 9 cm 2 0.05/0.14 71 (32) 27 (17) 45 (21) 16 cm 2 0.05/0.25 71 (30) 37 (17) 50 (21) Estrone 9 cm 2 0.05/0.14 72 (23) 49 (19) 54 (19) 16 cm 2 0.05/0.25 78 (22) 58 (22) 60 (18) Norethindrone: Progestins used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Norethindrone steady-state concentrations are attained within 24 hours of application of the CombiPatch transdermal delivery systems. Minimal fluctuations in serum norethindrone concentrations are observed following CombiPatch treatment, indicating consistent hormone delivery over the application interval. Serum concentrations of norethindrone increase linearly with increasing doses of NETA. In 1 study, serum concentrations of norethindrone were measured in 40 healthy, postmenopausal women throughout 3 consecutive CombiPatch applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table 2. Table 2. Mean (SD) Serum Norethindrone Concentrations (pg/mL) at Steady-State System Size Dose Estradiol/NETA (mg per day) C max C min C avg 9 cm 2 0.05/0.14 617 (341) 386 (137) 489 (244) 16 cm 2 0.05/0.25 1060 (543) 686 (306) 840 (414) Distribution Estradiol: 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. Norethindrone: In plasma, norethindrone is bound approximately 90 percent to SHBG and albumin. Metabolism Estradiol: 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 a 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 intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Norethindrone: NETA is hydrolyzed to the active moiety, norethindrone, in most tissues including skin and blood. Norethindrone is primarily metabolized in the liver. Excretion Estradiol: Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Estradiol has a short elimination half-life of approximately 2 to 3 hours; therefore, a rapid decline in serum levels is observed after the CombiPatch estradiol/NETA transdermal system is removed. Within 4 to 8 hours serum estradiol concentrations return to untreated, postmenopausal levels (less than 20 pg/mL). Concentration data from clinical trials indicate that the pharmacokinetics of estradiol did not change over time, suggesting no evidence of the accumulation of estradiol following extended patch wear periods (up to 1 year). Norethindrone: The elimination half-life of norethindrone is reported to be 6 to 8 hours. Norethindrone serum concentrations diminish rapidly and are less than 50 pg/mL within 48 hours after removal of the CombiPatch transdermal delivery system. Concentration data from clinical trials indicate that the pharmacokinetics of norethindrone did not change over time, suggesting no evidence of the accumulation of norethindrone following extended patch wear periods (up to 1 year). Special Populations No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Effects on Vasomotor Symptoms In 2 clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in postmenopausal women (n=332), CombiPatch was administered for 3 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, CombiPatch was applied throughout the 3 cycles, replacing the system twice weekly. In the Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle ® 0.05 mg) was applied twice weekly during the first 14 days of a 28-day cycle; CombiPatch was applied for the remaining 14 days of the cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from baseline to endpoint with either the Continuous Combined or Continuous Sequential administration of CombiPatch at all doses as compared to placebo (intent-to-treat population). (See Tables 3 and 4 ) Table 3. Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch Continuous Combined Transdermal Therapy 1 Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA). 2 Represents the milligrams of estradiol/NETA delivered daily by each system. 3 Population represents those patients who had baseline and endpoint observations. 4 The intensity of hot flushes was evaluated on a scale of 0 to 9 (none=0, mild=1-3, moderate= 4-6, severe=7-9). 5 P-value versus placebo = <0.001. 6 Total number of patients with available data is 56. 7 Total number of patients with available data is 50. CombiPatch Continuous Combined Placebo Adjusted Mean Change from Baseline 1 0.05/0.14 mg per day 2 n=57 0.05/0.25 mg per day 2 n=52 n=51 Number of Hot Flushes 3 -9.3 5 -8.9 5 -6.2 Daily Intensity of Hot Flushes 3,4 -4.6 5,6 -5.0 5 -2.8 7 Table 4. Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch Continuous Sequential Transdermal Therapy 1 Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA). 2 Represents the milligrams of estradiol/NETA delivered daily by each system. 3 Population represents those patients who had baseline and endpoint observations. 4 The intensity of hot flushes was evaluated on a scale of 0 to 9 (none=0, mild=1-3, moderate= 4-6, severe=7-9). 5 P-value versus placebo = <0.001. CombiPatch ® Continuous Combined Placebo Adjusted Mean Change from Baseline 1 0.05/0.14 mg per day 2 n=54 0.05/0.25 mg per day 2 n=59 n=53 Number of Hot Flushes 3 -9.3 5 -9.5 5 -5.5 Daily Intensity of Hot Flushes 3,4 -4.4 5 -4.5 5 -2.1 Effects on the Endometrium The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue. Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the efficacy of estrogen therapy for its approved indications. CombiPatch was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after 1 year of therapy in two clinical trials. Nine hundred fifty-five (955) postmenopausal women (with intact uteri) were treated with (i) a continuous regimen of CombiPatch alone ( Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch transdermal system ( Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was significantly less after 1 year of therapy with either CombiPatch regimen than with the estradiol-only transdermal system. Tables 5 and 6 summarize these results (intent-to-treat populations). Table 5. Incidence of Endometrial Hyperplasia in a Continuous Combined CombiPatch Regimen 1 Represents milligrams of estradiol/NETA delivered daily by each system. 2 Biopsy after 12 cycles of treatment or hyperplasia before cycle 12. 3 Comparison of continuous combined regimen versus estradiol-only patch was significant (p <0.001). 4 This patient had hyperplasia at baseline. 5 One of 39 patients had hyperplasia in an endometrial polyp. CombiPatch Continuous Combined Vivelle Continuous 0.05/0.14 mg per day 1 0.05/0.25 mg per day 1 0.05 mg per day Number of Patients with Biopsies 2 123 98 103 Number (%) of Patients with Hyperplasia 1 (<1%) 3 1 (1%) 3,4 39 (38%) 5 Table 6. Incidence of Endometrial Hyperplasia in a Continuous Sequential CombiPatch Regimen 1 Represents milligrams of estradiol/NETA delivered daily by each system. 2 Biopsy after 12 cycles of treatment or hyperplasia before cycle 12. 3 Comparison of continuous sequential regimen versus estradiol-only patch was significant (p <0.001). 4 This patient had hyperplasia at baseline. 5 This patient had hyperplasia in an endometrial polyp. CombiPatch Continuous Sequential Vivelle Continuous 0.05/0.14 mg per day 1 0.05/0.25 mg per day 1 0.05 mg per day Number of Patients with Biopsies 2 117 114 115 Number (%) of Patients with Hyperplasia 1 (<1%) 3,4 1 (<1%) 3,5 23 (20%) Effects on Uterine Bleeding or Spotting With the Continuous Combined regimen, of the women treated with CombiPatch and who completed the 1-year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 through 12 was 53 percent and 39 percent for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. Women who experienced bleeding usually characterized it as light (intensity of 1.3 on a scale of 1 to 4) with a duration of 4 and 6 days for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. (See Figure 1 ) Figure 1. Incidence of Cumulative Amenorrhea* in CombiPatch Continuous Combined Transdermal Therapy by Cycle Over a 1-Year Period (Intent-to-Treat Population) *Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sustained to the end of the study. Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) [defined as nonfatal MI, silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79 years; 83.9 percent white, 6.8 percent black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 7 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 7. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals (CI) unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. Event Relative Risk CE/MPA vs. Placebo (95% nCI c ) CE/MPA n=8,506 Placebo n=8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99–1.53) 41 34 Nonfatal MI 1.28 (1.00–1.63) 31 25 CHD death 1.10 (0.70–1.75) 8 8 All strokes 1.31 (1.03–1.68) 33 25 Ischemic stroke 1.44 (1.09–1.90) 26 18 Deep vein thrombosis d 1.95 (1.43–2.67) 26 13 Pulmonary embolism 2.13 (1.45–3.11) 18 8 Invasive breast cancer e 1.24 (1.01–1.54) 41 33 Colorectal cancer 0.61 (0.42–0.87) 10 16 Endometrial cancer d 0.81 (0.48–1.36) 6 7 Cervical cancer d 1.44 (0.47–4.42) 2 1 Hip fracture 0.67 (0.47–0.96) 11 16 Vertebral fractures d 0.65 (0.46–0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59–0.85) 44 62 Total fractures d 0.76 (0.69–0.83) 152 199 Overall mortality f 1.00 (0.83–1.19) 52 52 Global Index g 1.13 (1.02–1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI 0.44 to 1.07)]. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79 years; 75.3 percent white, 15.1 percent black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 8 . Table 8. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI a a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi . b Nominal CI unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index”. e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. Event Relative Risk CE vs. Placebo (95% nCI b ) CE n=5,310 Placebo n=5,429 Absolute Risk per 10,000 Women-Years CHD events c 0.95 (0.78–1.16) 54 57 Nonfatal MI c 0.91 (0.73–1.14) 40 43 CHD death c 1.01 (0.71–1.43) 16 16 All strokes c 1.33 (1.05–1.68) 45 33 Ischemic stroke c 1.55 (1.19–2.01) 38 25 Deep vein thrombosis c,d 1.47 (1.06–2.06) 23 15 Pulmonary embolism c 1.37 (0.90–2.07) 14 10 Invasive breast cancer c 0.80 (0.62–1.04) 28 34 Colorectal cancer e 1.08 (0.75–1.55) 17 16 Hip fracture c 0.65 (0.45–0.94) 12 19 Vertebral fractures c,d 0.64 (0.44–0.93) 11 18 Lower arm/wrist fractures c,d 0.58 (0.47–0.72) 35 59 Total fractures c,d 0.71 (0.64–0.80) 144 197 Death due to other causes e,f 1.08 (0.88–1.32) 53 50 Overall mortality c,d 1.04 (0.88–1.22) 79 75 Global Index g 1.02 (0.92–1.13) 206 201 For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9  The absolute excess risk of events included in the “global index” was a nonsignificant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years (see Table 8 ). Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess was present in all subgroups of women examined. 10 (see Table 8 ). Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age, a nonsignificant trend toward reduced risk for CHD [HR 0.63 (95 percent, CI 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)]. Women’s Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Probable Dementia and PRECAUTIONS , Geriatric Use ) The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Probable Dementia and PRECAUTIONS , Geriatric Use ) When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Probable Dementia and PRECAUTIONS , Geriatric Use ) Chart

PRINCIPAL DISPLAY PANEL - NDC - 68968-0514-8 CombiPatch Count - 50/140 NDC 68968-0514-8 Includes 8 Systems See New Storage Requirements Combipatch ® 50/140 (estradiol/norethindrone acetate transdermal system) 0.05/0.14 mg per day Noven www.combipatch.com Twice-Weekly Rx Only Combipatch ® 50/140 (estradiol/norethindrone acetate transdermal system) 0.05/0.14 mg per day Twice-Weekly Rx Only Contains 0.62 mg estradiol USP and 2.7 mg norethindrone acetate (NETA) USP to provide 0.05/0.14 mg of estradiol/NETA per day. Inactive components : a silicone and acrylic-based multi-polymeric adhesive, povidone USP, oleic acid NF, polyolefin laminate backing, polyester release liner and dipropylene glycol. Dosage and Administration: For transdermal use only. See package insert. Allow patch to reach room temperature before application. DO NOT STORE UNPOUCHED. Keep out of the reach of children. Store Combipatch ® refrigerated at 36°F to 46°F (2°C to 8°C) See side panel for lot number and expiration date. www.combipatch.com N3 68968-0514-8 0 302391-4 Noven PLEASE READ THIS BEFORE APPLYING PATCH. Allow patch to reach room temperature before application. See reverse side for patient instructions. pull To open here LOT/EXP GTIN 00368968051480 969864 Mfd. By: Noven Pharmaceuticals, Inc. Miami, Florida 33186 Dist. By Noven Therapeutics, LLC Miami, Florida 33186 Combi patch Count - 50/140