estradiol

RECENT MAJOR CHANGES Warnings and Precautions (5.2) 12/2023

1 INDICATIONS AND USAGE Estradiol transdermal system continuous delivery (once-weekly) is indicated for: Estradiol transdermal system continuous delivery (once-weekly) is an estrogen indicated for: • Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) • Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) Limitations of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products. • Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure ( 1.3 ) • Prevention of Postmenopausal Osteoporosis ( 1.4 ) Limitations 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. 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products. 1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure 1.4 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 to use 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 estrogen-alone or in combination with a progestogen at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. • Start therapy with estradiol transdermal system (twice-weekly) 0.0375 mg/day applied to the skin twice weekly for the treatment of moderate to severe vasomotor symptoms due to menopause or moderate to severe symptoms of vulvar and vaginal atrophy symptoms due to menopause. Dosage adjustment should be guided by the clinical response ( 2.1 , 2.2 , 2.3 ) • Start therapy with estradiol transdermal system (twice-weekly) 0.025 mg/day for the prevention of postmenopausal osteoporosis ( 2.4 ) • Place estradiol transdermal system (twice-weekly) on a clean, dry area of the lower abdomen or buttocks. Do not apply estradiol transdermal system (twice-weekly) to the breasts ( 2.5 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause Start therapy with estradiol transdermal system (twice-weekly) 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on the clinical response. Initiate estradiol transdermal system (twice-weekly) at once in a woman not currently taking oral estrogens or in a woman switching from another estradiol transdermal therapy. In women who are currently taking oral estrogens, initiate treatment with estradiol transdermal system (twice-weekly) 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Attempts to taper or discontinue estradiol transdermal system (twice-weekly) at 3 to 6-month intervals. Give estradiol transdermal system (twice-weekly) continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give estradiol transdermal system (twice-weekly) on a cyclic schedule (for example, 3 weeks on estradiol transdermal system (twice-weekly) followed by 1 week off estradiol transdermal system (twice-weekly)). 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy Due to Menopause Start therapy with estradiol transdermal system (twice-weekly) 0.0375 mg per day applied to the skin twice weekly. Dosage adjustment should be guided by the clinical response. Attempts to taper or discontinue estradiol transdermal system (twice-weekly) at 3 to 6-month intervals. In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with estradiol transdermal system (twice-weekly) may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with estradiol transdermal system (twice-weekly) 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Give estradiol transdermal system (twice-weekly) continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give estradiol transdermal system (twice-weekly) on a cyclic schedule (for example, 3 weeks on estradiol transdermal system (twice-weekly) followed by 1 week off estradiol transdermal system (twice-weekly)). 2.3 Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure 2.4 Prevention of Postmenopausal Osteoporosis Start therapy with estradiol transdermal system (twice-weekly) 0.025 mg per day applied to the skin twice weekly. In women not currently taking oral estrogens or in women switching from another e …

3 DOSAGE FORMS AND STRENGTHS Estradiol Transdermal System, USP Continuous Delivery (Once-Weekly) is available as 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.06 mg/day, 0.075 mg/day or 0.1 mg/day of estradiol. • The 0.025 mg/day is available as a 7.75 cm 2 system containing estradiol, USP hemihydrate equivalent to 0.97 mg of estradiol for a nominal in vivo delivery of 0.025 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.025 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. • The 0.0375 mg/day is available as an 11.625 cm 2 system containing estradiol, USP hemihydrate equivalent to 1.46 mg of estradiol for a nominal in vivo delivery of 0.0375 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.0375 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. • The 0.05 mg/day is available as a 15.5 cm 2 system containing estradiol, USP hemihydrate equivalent to 1.94 mg of estradiol for a nominal in vivo delivery of 0.05 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.05 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. • The 0.06 mg/day is available as an 18.6 cm 2 system containing estradiol, USP hemihydrate equivalent to 2.33 mg of estradiol for a nominal in vivo delivery of 0.06 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.06 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. • The 0.075 mg/day is available as a 23.25 cm 2 system containing estradiol, USP hemihydrate equivalent to 2.91 mg of estradiol for a nominal in vivo delivery of 0.075 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.075 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. • The 0.1 mg/day is available as a 31 cm 2 system containing estradiol, USP hemihydrate equivalent to 3.88 mg of estradiol for a nominal in vivo delivery of 0.1 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.1 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. • Transdermal system: 0.025 mg per day, 0.0375 mg per day, 0.05 mg per day, 0.06 mg per day, 0.075 mg per day and 0.1 mg per day ( 3 )

4 CONTRAINDICATIONS Estradiol transdermal system continuous delivery (once-weekly) is contraindicated in women with any of the following conditions: • Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2) ] • Breast cancer or 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 or MI), or a history of these conditions [see Warnings and Precautions (5.1) ] • Known anaphylactic reaction, or angioedema, or hypersensitivity to estradiol transdermal system continuous delivery (once-weekly) • 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, or angioedema, or hypersensitivity to estradiol transdermal system continuous delivery (once-weekly) ( 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: 1. Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] 2. Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] The most common adverse reactions (≥ 10%) with estradiol transdermal system (twice-weekly) are: headache, breast tenderness, nasopharyngitis, sinusitis, sinus headache, upper respiratory tract infection, back pain, depression, and irregular vaginal bleeding or spotting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 the revised formulation of estradiol transdermal system (twice-weekly). The revised formulation of estradiol transdermal system (twice-weekly) is bioequivalent to the original formulation of estradiol transdermal system (twice-weekly). The following adverse reactions have been reported with the original formulation of estradiol transdermal system (twice-weekly) therapy: Table 1. Summary of Most Frequently Reported Adverse Reactions Regardless of Relationship Reported at a Frequency ≥ 5% Estradiol Transdermal System (Twice-Weekly) Placebo 0.025 mg/day Represents milligrams of estradiol delivered daily by each system. 0.0375 mg/day 0.05 mg/day 0.075 mg/day 0.1 mg/day (N = 47) (N = 130) (N = 103) (N = 46) (N = 132) (N = 157) N (%) N (%) N (%) N (%) N (%) 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 Application site erythema and application site irritation were observed in a small number of patients (3.2% or less of patients across treatment groups). Influenza-like illness 3 (6.4) 6 (4.6) 8 (7.8) 0 3 (2.3) 10 (6.4) Pain NOS NOS represents not otherwise specified. 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 NEC represents not elsewhere classified. 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) 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of estradiol transdermal system (twice-weekly). Because these reactions are reported voluntari …

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 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Estradiol transdermal system continuous delivery (once-weekly) is not indicated for use in pregnancy. There are no data with the use of estradiol transdermal system continuous delivery (once-weekly) 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 continuous delivery (once-weekly) and any potential adverse effects on the breastfed child from estradiol transdermal system continuous delivery (once-weekly) or from the underlying maternal condition. 8.4 Pediatric Use In general, estradiol transdermal system continuous delivery (once-weekly) is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone metabolism and effects on epiphyseal centers is recommended during estrogen administration. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing estradiol transdermal system continuous delivery (once-weekly) to determine whether those over 65 years of age differ from younger subjects in their response to estradiol transdermal system continuous delivery (once-weekly). 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 developing 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 (14.4) ] .

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, which is 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 levels of these hormones seen in postmenopausal women.

11 DESCRIPTION Estradiol Transdermal System, USP is designed to release estradiol continuously upon application to intact skin. Six (7.5, 11.25, 15, 18, 22.5 and 30 cm 2 ) systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.06, 0.075 or 0.1 mg respectively of estradiol per day. The period of use is 7 days. Each system has a contact surface area of either 7.5, 11.25, 15, 18, 22.5 or 30 cm 2 , and contains 1.888, 2.832, 3.777, 4.532, 5.665 or 7.553 mg of estradiol USP respectively. The composition of the systems per unit area is identical. Estradiol USP is a white or creamy white, small crystals or crystalline powder, odorless, stable in air and hygroscopic. Estradiol USP is chemically described as estra-1,3,5(10)-triene-3, 17ß-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.38. The structural formula is: The Estradiol Transdermal System, USP comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are: A translucent polyethylene film. An acrylate adhesive matrix containing estradiol USP. A protective liner of silicone coated polyester film is attached to the adhesive surface and must be removed before the system can be used. Cross Section of the System Estradiol Transdermal System, USP is packaged with additional pieces of protective film above and below the system within each pouch. These are discarded at the time of use. The active component of the system is estradiol USP. The remaining components of the system (acrylic adhesive, colloidal silicon dioxide, ethyl oleate, glyceryl monolaurate, isopropyl myristate, povidone and polyethylene backing) are pharmacologically inactive. FDA approved drug release test specifications differ from USP. Estradiol Transdermal System Estradiol Transdermal System

10 OVERDOSAGE Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of estradiol transdermal system continuous delivery (once-weekly) therapy with institution of appropriate symptomatic care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol Transdermal System, USP Continuous Delivery (Once-Weekly) is available as 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.06 mg/day, 0.075 mg/day or 0.1 mg/day of estradiol. The 0.025 mg/day is available as a 7.75 cm 2 system containing estradiol, USP hemihydrate equivalent to 0.97 mg of estradiol for a nominal in vivo delivery of 0.025 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.025 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. They are available as follows: NDC 0378-3349-99 carton containing 4 transdermal systems The 0.0375 mg/day is available as an 11.625 cm 2 system containing estradiol, USP hemihydrate equivalent to 1.46 mg of estradiol for a nominal in vivo delivery of 0.0375 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.0375 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. NDC 0378-3360-99 carton containing 4 transdermal systems The 0.05 mg/day is available as a 15.5 cm 2 system containing estradiol, USP hemihydrate equivalent to 1.94 mg of estradiol for a nominal in vivo delivery of 0.05 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.05 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. NDC 0378-3350-99 carton containing 4 transdermal systems The 0.06 mg/day is available as an 18.6 cm 2 system containing estradiol, USP hemihydrate equivalent to 2.33 mg of estradiol for a nominal in vivo delivery of 0.06 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.06 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. NDC 0378-3361-99 carton containing 4 transdermal systems The 0.075 mg/day is available as a 23.25 cm 2 system containing estradiol, USP hemihydrate equivalent to 2.91 mg of estradiol for a nominal in vivo delivery of 0.075 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.075 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. NDC 0378-3351-99 carton containing 4 transdermal systems The 0.1 mg/day is available as a 31 cm 2 system containing estradiol, USP hemihydrate equivalent to 3.88 mg of estradiol for a nominal in vivo delivery of 0.1 mg of estradiol per day. Each patch consists of a round inner disk centered on a round peach color outer disk with “Estradiol 0.1 mg/day (Once-Weekly)” printed on the outer disk in brown. Each patch is contained in a square, notched pouch with printed paper on both sides. The pouch is imprinted with the lot number and expiration date. NDC 0378-3352-99 carton containing 4 transdermal systems 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°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 containe …