estradiol

Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 02/2024

1 INDICATIONS AND USAGE ESTRADIOL TRANSDERMAL SYSTEM is indicated for: ESTRADIOL TRANSDERMAL SYSTEM is an estrogen indicated for: Treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ) Prevention of postmenopausal osteoporosis ( 1.2 ) Limitation of Use When prescribing solely for the treatment of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis. 1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.

2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus, does not need a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.14 )] . Use of estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. Start therapy with ESTRADIOL TRANSDERMAL SYSTEM 0.0375 mg per day applied to the skin twice weekly for the treatment of moderate to severe vasomotor symptoms due to menopause. Dosage adjustment should be guided by the clinical response ( 2.1 ) Start therapy with ESTRADIOL TRANSDERMAL SYSTEM 0.025 mg per day applied to the skin twice weekly for the prevention of postmenopausal osteoporosis. The dose may be adjusted as necessary ( 2.2 ) Place ESTRADIOL TRANSDERMAL SYSTEM on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply ESTRADIOL TRANSDERMAL SYSTEM to the breasts ( 2.3 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with ESTRADIOL TRANSDERMAL SYSTEM 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on clinical response. Attempt to taper or discontinue the medication at 3 to 6 month intervals. 2.2 Prevention of Postmenopausal Osteoporosis due to Menopause 2.3 Application Instructions Place the adhesive side of ESTRADIOL TRANSDERMAL SYSTEM on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply ESTRADIOL TRANSDERMAL SYSTEM to the breasts. Replace ESTRADIOL TRANSDERMAL SYSTEM twice weekly (every 3-4 days). Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site. Select an area for application that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact with the skin, especially around the edges. In the event that a system falls off, reapply the same system or apply a new system to another location. If a woman has forgotten to apply ESTRADIOL TRANSDERMAL SYSTEM, have her apply a new system as soon as possible. Apply the new system on the original treatment schedule. The interruption of treatment in women taking ESTRADIOL TRANSDERMAL SYSTEM might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.

3 DOSAGE FORMS AND STRENGTHS Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day. Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day ( 3 )

4 CONTRAINDICATIONS ESTRADIOL TRANSDERMAL SYSTEM is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [See Warnings and Precautions ( 5.2 )] . Breast cancer or a history of breast cancer [See Warnings and Precautions ( 5.2 )] . Estrogen-dependent neoplasia [See Warnings and Precautions ( 5.2 )] . Active DVT, PE, or a history of these conditions [See Warnings and Precautions ( 5.1 )] . Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [See Warnings and Precautions ( 5.1 )] . Known anaphylactic reaction or angioedema or hypersensitivity to ESTRADIOL TRANSDERMAL SYSTEM Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) Estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE, or a history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction, angioedema, or hypersensitivity to ESTRADIOL TRANSDERMAL SYSTEM( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders [see Boxed Warnings and Warnings and Precautions ( 5.1 )] Malignant Neoplasms [see Boxed Warnings and Warnings and Precautions ( 5.2 )] The most common adverse reactions (greater than or equal to 5 percent) with ESTRADIOL TRANSDERMAL SYSTEM are: headache, breast tenderness, back pain, pain in limb, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Noven at 1-800-455-8070 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience 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. There were no clinical trials conducted with ESTRADIOL TRANSDERMAL SYSTEM. ESTRADIOL TRANSDERMAL SYSTEM is bioequivalent to Vivelle ® . The following adverse reactions are reported with Vivelle therapy: Table 1: Summary of Most Frequently Reported Adverse Reactions (Vivelle versus Placebo) Regardless of Relationship Reported at a Frequency ≥ 5 Percent †Represents milligrams of estradiol delivered daily by each system *NOS represents not otherwise specified **NEC represents not elsewhere classified ***Application site erythema and application site irritation were observed in 3.2% or less of patients across treatment groups. Vivelle 0.025 mg/ day† (N=47) N (%) Vivelle 0.0375 mg/ day† (N=130) N (%) Vivelle 0.05 mg/ day† (N=103) N (%) Vivelle 0.075 mg/ day† (N=46) N (%) Vivelle 0.1 mg/ day† (N=132) N (%) Placebo (N=157) N (%) Gastrointestinal disorders Constipation 2 (4.3) 5 (3.8) 4 (3.9) 3 (6.5) 2 (1.5) 4 (2.5) Dyspepsia 4 (8.5) 12 (9.2) 3 (2.9) 2 (4.3) 0 10 (6.4) Nausea 2 (4.3) 8 (6.2) 4 (3.9) 0 7 (5.3) 5 (3.2) General disorders and administration site conditions *** Influenza-like illness 3 (6.4) 6 (4.6) 8 (7.8) 0 3 (2.3) 10 (6.4) Pain NOS * 0 8 (6.2) 0 2 (4.3) 7 (5.3) 7 (4.5) Infections and infestations Influenza 4 (8.5) 4 (3.1) 6 (5.8) 0 10 (7.6) 14 (8.9) Nasopharyngitis 3 (6.4) 16 (12.3) 10 (9.7) 9 (19.6) 11 (8.3) 24 (15.3) Sinusitis NOS * 4 (8.5) 17 (13.1) 13 (12.6) 3 (6.5) 7 (5.3) 16 (10.2) Upper respiratory tract infection NOS * 3 (6.4) 8 (6.2) 11 (10.7) 4 (8.7) 6 (4.5) 9 (5.7) Investigations Weight increased 4 (8.5) 5 (3.8) 2 (1.9) 2 (4.3) 0 3 (1.9) Musculoskeletal and connective tissue disorders Arthralgia 0 11 (8.5) 4 (3.9) 2 (4.3) 5 (3.8) 9 (5.7) Back pain 4 (8.5) 10 (7.7) 9 (8.7) 4 (8.7) 14 (10.6) 10 (6.4) Neck pain 3 (6.4) 4 (3.1) 4 (3.9) 0 6 (4.5) 2 (1.3) Pain in limb 0 10 (7.7) 7 (6.8) 2 (4.3) 6 (4.5) 9 (5.7) Nervous system disorders Headache NOS * 7 (14.9) 35 (26.9) 32 (31.1) 23 (50.0) 34 (25.8) 37 (23.6) Sinus headache 0 12 (9.2) 5 (4.9) 5 (10.9) 2 (1.5) 8 (5.1) Psychiatric disorders Anxiety NEC ** 3 (6.4) 5 (3.8) 0 0 2 (1.5) 4 (2.5) Depression 5 (10.6) 4 (3.1) 7 (6.8) 0 4 (3.0) 6 (3.8) Insomnia 3 (6.4) 6 (4.6) 4 (3.9) 2 (4.3) 2 (1.5) 9 (5.7) Reproductive system and breast disorders Breast tenderness 8 (17.0) 10 (7.7) 8 (7.8) 3 (6.5) 17 (12.9) 0 Dysmenorrhea 0 0 0 3 (6.5) 0 0 Intermenstrual bleeding 3 (6.4) 9 (6.9) 6 (5.8) 0 14 (10.6) 7 (4.5) Respiratory, thoracic and mediastinal disorders Sinus congestion 0 4 (3.1) 3 (2.9) 3 (6.5) 6 (4.5) 7 (4.5) Vascular disorders Hot flushes NOS * 3 (6.4) 0 3 (2.9) 0 0 6 (3.8) Hypertension NOS * 2 (4.3) 0 3 (2.9) 0 0 2 (1.3) During the clinical pharmacology studies with ESTRADIOL TRANSDERMAL SYSTEM, 35 percent or less of subjects experienced barely perceptible erythema. No transdermal systems were removed due to irritation. Three subjects (2.2 percent) reported mild discomfort while wearing ESTRADIOL TRANSDERMAL SYSTEM (N=136). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ESTRADIOL TRANSDERMAL SYSTEM. Because …

7 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 adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7.1 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary ESTRADIOL TRANSDERMAL SYSTEM is not indicated for use in pregnancy. There are no data with the use of ESTRADIOL TRANSDERMAL SYSTEM in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ESTRADIOL TRANSDERMAL SYSTEM and any potential adverse effects on the breastfed child from ESTRADIOL TRANSDERMAL SYSTEM or from the underlying maternal condition. 8.4 Pediatric Use ESTRADIOL TRANSDERMAL SYSTEM is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing ESTRADIOL TRANSDERMAL SYSTEM to determine whether those over 65 years of age differ from younger subjects in their response to ESTRADIOL TRANSDERMAL SYSTEM. The Women’s Health Initiative 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 ( 14.3 )] . 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 ( 14.3 )] . 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 probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.4 )] . 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 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] .

12.1 Mechanism of Action 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, two 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 concentrations of these hormones seen in postmenopausal women.

11 DESCRIPTION ESTRADIOL TRANSDERMAL SYSTEM contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of ESTRADIOL TRANSDERMAL SYSTEM are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via the skin. Each corresponding system has an active surface area of 1.65, 2.48, 3.30, 4.95, or 6.6 cm 2 and contains 0.41, 0.62, 0.83, 1.24, or 1.65 mg of estradiol USP, respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The structural formula is The molecular formula of estradiol is C 18 H 24 O 2 . The molecular weight is 272.39 ESTRADIOL TRANSDERMAL SYSTEM is comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a polyolefin laminate backing (2) an adhesive formulation containing estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive. chemical structure layers

10 OVERDOSAGE Overdosage of estrogen 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 ESTRADIOL TRANSDERMAL SYSTEM therapy with institution of appropriate symptomatic care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ESTRADIOL TRANSDERMAL SYSTEM, 0.025 mg per day - each 1.65 cm 2 system contains 0.41 mg of estradiol USP for nominal* delivery of 0.025 mg of estradiol per day. Patient Calendar Pack of 8 Systems.........................................NDC 68968-3425-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.0375 mg per day - each 2.48 cm 2 system contains 0.62 mg of estradiol USP for nominal* delivery of 0.0375 mg of estradiol per day. Patient Calendar Pack of 8 Systems.........................................NDC 68968-3437-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.05 mg per day - each 3.3 cm 2 system contains 0.83 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day. Patient Calendar Pack of 8 Systems........................................NDC 68968-3450-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.075 mg per day - each 4.95 cm 2 system contains 1.24 mg of estradiol USP for nominal* delivery of 0.075 mg of estradiol per day. Patient Calendar Pack of 8 Systems........................................NDC 68968-3475-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.1 mg per day - each 6.6 cm 2 system contains 1.65 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day. Patient Calendar Pack of 8 Systems........................................NDC 68968-3410-8 *See Description 16.2 Storage and Handling Store at room temperature 68°F to 77°F (20°C to 25°C); excursions permitted between 15°C and 30°C (59°F and 86°F). [ See USP Controlled Room Temperature ] Do not store unpouched. Apply immediately upon removal from the protective pouch. Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.

16.1 How Supplied ESTRADIOL TRANSDERMAL SYSTEM, 0.025 mg per day - each 1.65 cm 2 system contains 0.41 mg of estradiol USP for nominal* delivery of 0.025 mg of estradiol per day. Patient Calendar Pack of 8 Systems.........................................NDC 68968-3425-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.0375 mg per day - each 2.48 cm 2 system contains 0.62 mg of estradiol USP for nominal* delivery of 0.0375 mg of estradiol per day. Patient Calendar Pack of 8 Systems.........................................NDC 68968-3437-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.05 mg per day - each 3.3 cm 2 system contains 0.83 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day. Patient Calendar Pack of 8 Systems........................................NDC 68968-3450-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.075 mg per day - each 4.95 cm 2 system contains 1.24 mg of estradiol USP for nominal* delivery of 0.075 mg of estradiol per day. Patient Calendar Pack of 8 Systems........................................NDC 68968-3475-8 ESTRADIOL TRANSDERMAL SYSTEM, 0.1 mg per day - each 6.6 cm 2 system contains 1.65 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day. Patient Calendar Pack of 8 Systems........................................NDC 68968-3410-8 *See Description