CombiPatch (estradiol/norethindrone acetate transdermal system)

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION 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), …

CONTRAINDICATIONS 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.

ADVERSE REACTIONS See BOXED WARNING , WARNINGS , and PRECAUTIONS . Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 9. All Adverse Reactions Regardless of Relationship Reported at a Frequency of Greater than or Equal to 5 percent with CombiPatch VASOMOTOR SYMPTOM STUDIES CombiPatch 0.05/0.14 mg per day† CombiPatch 0.05/0.25 mg per day† Placebo n=113 n=112 n=107 Body as a Whole 46% 48% 41% Abdominal Pain 7% 6% 4% Accidental Injury 4% 5% 8% Asthenia 8% 12% 4% Back Pain 11% 9% 5% Flu Syndrome 9% 5% 7% Headache 18% 20% 20% Pain 6% 4% 9% Digestive 19% 23% 24% Diarrhea 4% 5% 7% Dyspepsia 1% 5% 5% Flatulence 4% 5% 4% Nausea 11% 8% 7% Nervous 16% 28% 28% Depression 3% 5% 9% Insomnia 3% 6% 7% Nervousness 3% 5% 1% Respiratory 24% 38% 26% Pharyngitis 4% 10% 2% Respiratory Disorder 7% 12% 7% Rhinitis 7% 13% 9% Sinusitis 4% 9% 9% Skin and Appendages 8% 17% 16% Application Site Reaction* 2% 6% 4% Urogenital 54% 63% 28% Breast Pain 25% 31% 7% Dysmenorrhea 20% 21% 5% Leukorrhea 5% 5% 3% Menstrual Disorder 6% 12% 2% Papanicolaou Smear Suspicious 8% 4% 5% Vaginitis 6% 13% 5% †Represents milligrams of estradiol/NETA delivered daily by each system. *Application site reactions includes localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, skin discoloration, skin pigmentation, swelling, urticaria, and vesicles. Table 10. All Adverse Reactions Regardless of Relationship Reported at a Frequency of Greater than or Equal to 5 percent with CombiPatch ENDOMETRIAL HYPERPLASIA STUDIES CombiPatch 0.05/0.14 mg per day† n=325 CombiPatch 0.05/0.25 mg per day† n=312 Vivelle 0.05 mg per day n=318 Body as a Whole 61% 60% 59% Abdominal Pain 12% 14% 16% Accidental Injury 10% 11% 8% Asthenia 10% 13% 11% Back Pain 15% 14% 13% Flu Syndrome 14% 10% 7% Headache 25% 17% 21% Infection 5% 3% 3% Pain 19% 15% 13% Digestive 42% 32% 31% Constipation 2% 5% 3% Diarrhea 14% 9% 7% Dyspepsia 8% 6% 5% Flatulence 7% 5% 6% Nausea 8% 12% 11% Tooth Disorder 6% 4% 1% Metabolic and Nutritional Disorders 12% 13% 11% Peripheral Edema 6% 6% 5% Musculoskeletal 17% 17% 15% Arthralgia 6% 6% 5% Nervous 33% 30% 28% Depression 8% 9% 8% Dizziness 6% 7% 5% Insomnia 8% 6% 4% Nervousness 5% 6% 3% Respiratory 45% 43% 40% Bronchitis 5% 3% 4% Pharyngitis 9% 9% 8% Respiratory Disorder 13% 9% 13% Rhinitis 19% 22% 17% Sinusitis 10% 12% 12% Skin and Appendages 38% 37% 31% Acne 4% 5% 4% Application Site Reaction* 20% 23% 17% Rash 6% 5% 3% Urogenital 71% 79% 74% Breast Enlargement 2% 7% 2% Breast Pain 34% 48% 40% Dysmenorrhea 30% 31% 19% Leukorrhea 10% 8% 9% Menorrhagia 2% 5% 9% Menstrual Disorder 17% 19% 14% Vaginal Hemorrhage 3% 6% 12% Vaginitis 9% 13% 13% †Represents milligrams of estradiol/NETA delivered daily by each system. *Application site reactions includes localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, skin discoloration, skin pigmentation, swelling, urticaria, and vesicles. Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of CombiPatch. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Endometrial hyperplasia, endocervical polyp, uterine leiomyomata, fallopian tube cyst, uterine spasms. Breast Breast cancer. Cardiovascular Hypertension, varicose veins. Gastrointestinal Jaundice cholestatic, cholelithiasis, gall bladder disorder, transaminases increased. Skin Skin discoloration. Central Nervous System Affect lability, libido disorder, migraine, vertig …

Drug Interactions 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.

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. 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

OVERDOSAGE Overdosage of estrogen or estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CombiPatch therapy with institution of appropriate symptomatic care.

HOW SUPPLIED 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°F to 46°F (2°C to 8°C). 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.