CombiPatch® (estradiol-norethindrone acetate transdermal system)

CombiPatch® (estradiol/norethindrone acetate transdermal system) WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER, AND PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use) Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast Cancer) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. 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. Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. (See WARNINGS, Malignant Neoplasms, Endometrial Cancer) Reference ID: 3375913 Page 2 Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia) The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders) The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. 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. DESCRIPTION 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. System Size Estradiol NETA1 Nominal Delivery Rate2 (mg per day) (mg) (mg) Estradiol / NETA 9 cm2 round 0.62 2.7 0.05/0.14 16 cm2 round 0.51 4.8 0.05/0.25 1NETA=norethindrone acetate. 2Based 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). Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular weight of estradiol is 272.39 and the molecular formula is C18H24O2. 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 C22H28O3. The structural formulas for estradiol and NETA are: Reference ID: 3375913 Page 3 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, oleyl alcohol, 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. CLINICAL PHARMACOLOGY 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. Reference ID: 3375913 Page 4 Pharmacokinetics 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) Cmax Cmin Cavg 9 cm2 0.05/0.14 71 (32) 27 (17) 45 (21) 16 cm2 0.05/0.25 71 (30) 37 (17) 50 (21) Estrone 9 cm2 0.05/0.14 72 (23) 49 (19) 54 (19) 16 cm2 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 Cmax Cmin Cavg (mg per day) 9 cm2 0.05/0.14 617 (341) 386 (137) 489 (244) 16 cm2 0.05/0.25 1060 (543) 686 (306) 840 (414) Reference ID: 3375913 Page 5 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 Phase II and III studies 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 Phase II and III studies 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. Reference ID: 3375913 Page 6 Drug Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin 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 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. CLINICAL STUDIES 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 CombiPatch Placebo Continuous Combined Adjusted Mean Change 0.05/0.14 0.05/0.25 n=51 from Baseline1 mg per day2 mg per day2 n=57 n=52 Number of Hot Flushes3 -9.35 -8.95 -6.2 Daily Intensity of Hot Flushes3,4 -4.65,6 -5.05 -2.87 1Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA). 2Represents the milligrams of estradiol/NETA delivered daily by each system. Reference ID: 3375913 Page 7 3Population represents those patients who had baseline and endpoint observations. 4The intensity of hot flushes was evaluated on a scale of 0 to 9 (none=0, mild=1-3, moderate= 4-6, severe=7-9). 5P value versus placebo = <0.001. 6Total number of patients with available data is 56. 7Total number of patients with available data is 50. 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 CombiPatch Placebo Continuous Sequential Adjusted Mean Change 0.05/0.14 0.05/0.25 n=53 from Baseline1 mg per day2 mg per day2 n=54 n=59 Number of Hot Flushes3 -9.35 -9.55 -5.5 Daily Intensity of Hot Flushes3,4 -4.45 -4.55 -2.1 1Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA). 2Represents the milligrams of estradiol/NETA delivered daily by each system. 3Population represents those patients who had baseline and endpoint observations. 4The intensity of hot flushes was evaluated on a scale of 0 to 9 (none=0, mild=1-3, moderate= 4-6, severe=7-9). 5P value versus placebo = <0.001. 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 2 Phase II 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 CombiPatch Vivelle Reference ID: 3375913 Page 8 Continuous Combined Continuous 0.05/0.14 0.05/0.25 0.05 mg per day1 mg per day1 mg per day Number of Patients with 123 98 103 Biopsies2 Number (%) of Patients with 1 (<1%)3 1 (1%)3,4 39 (38%)5 Hyperplasia 1Represents milligrams of estradiol/NETA delivered daily by each system. 2Biopsy after 12 cycles of treatment or hyperplasia before cycle 12. 3Comparison of continuous combined regimen versus estradiol-only patch was significant (p <0.001). 4This patient had hyperplasia at baseline. 5On