DOTTI

1 INDICATIONS AND USAGE DOTTI is indicated for: DOTTI 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 vaginal atrophy, 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 Limitations of Use : When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, 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 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.

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 DOTTI 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 DOTTI 0.025 mg/day for the prevention of postmenopausal osteoporosis (2.4) Place DOTTI on a clean, dry area of the lower abdomen or buttocks. Do not apply DOTTI to the breasts (2.5) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with DOTTI 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on the clinical response. Initiate DOTTI 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 DOTTI 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Attempts to taper or discontinue DOTTI at 3 to 6 month intervals. Give DOTTI continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give DOTTI on a cyclic schedule (for example, 3 weeks on DOTTI followed by 1 week off DOTTI). 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Start therapy with DOTTI 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 DOTTI at 3 to 6 month intervals. In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with DOTTI may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with DOTTI 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Give DOTTI continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give DOTTI on a cyclic schedule (for example, 3 weeks on DOTTI followed by 1 week off DOTTI). 2.3 Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure 2.4 Prevention of Postmenopausal Osteoporosis Start therapy with DOTTI 0.025 mg per day applied to the skin twice weekly. In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with DOTTI may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with DOTTI 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. DOTTI may be given continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, DOTTI may be given on a cyclic schedule (for example, 3 weeks on DOTTI followed by 1 week off DOTTI). 2.5 Application Instructions Place the adhesive side of DOTTI on a clean, dry area of the trunk of the body (including the abdomen or buttocks). Do not apply DOTTI to the breasts. Replace DOTTI twice weekly. Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site…

5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gallbladder disease (5.4) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5 , 5.6 , 5.9 , 5.10 ) Monitor thyroid function in women on thyroid replacement therapy (5.11 , 5.18) 5.1 Cardiovascular Disorders Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected. Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus). Stroke The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.3) ] . Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 stokes per 10,000 women-years) [see Clinical Studies (14.3 )] . The increase in risk was demonstrated after the first year and persisted. 1 Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected. Coronary Heart Disease The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.3) ] . Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) in CHD events in those women receiving daily CE (0.625 mg)–alone compared to placebo (8 versus 16 per 10,000 women-years). 1 The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) in CHD events in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.3) ] . In postmenopausal women with documented heart disease (n=2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in the HERS, the HERS II, and ov…

4 CONTRAINDICATIONS DOTTI 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 DOTTI 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 and MI), or a history of these conditions (4 , 5.1) Known anaphylactic reaction, or angioedema, or hypersensitivity with DOTTI (4 , 5.15) Hepatic impairment or disease (4 , 5.10) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)

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 )

8.1 Pregnancy Risk Summary DOTTI is not indicated for use in pregnancy. There are no data with the use of DOTTI 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 (estrogen 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 DOTTI and any potential adverse effects on the breastfed child from DOTTI or from the underlying maternal condition.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] The most common adverse reactions (≥10%) with DOTTI 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 Amneal Pharmaceuticals at 1-877-835-5472 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 DOTTI. DOTTI is bioequivalent to the original formulation of estradiol transdermal system. The following adverse reactions have been reported with the original formulation of estradiol transdermal system therapy: Table 1. Summary of Most Frequently Reported Adverse Reactions Regardless of Relationship Reported at a Frequency ≥5 Percent Estradiol 0.025 mg/day † (N=47) N (%) Estradiol 0.0375 mg/day † (N=130) N (%) Estradiol 0.05 mg/day † (N=103) N (%) Estradiol 0.075 mg/day † (N=46) N (%) Estradiol 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) † 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 a small number of patients (3.2% or less of patients across treatment groups). 6.2 Post-marketing Experience The following additional adverse reactions have been identified during post-approval use of DOTTI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Vaginal hemorrhage and abnormal wit…