Evamist

1 INDICATIONS AND USAGE Evamist is an estrogen indicated for the treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause.

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 , 5.15 )] . Use 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. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. • Start therapy with one spray of Evamist once daily each morning to forearm ( 2.1 ) • Dosage adjustment to two or three sprays of Evamist should be guided by the clinical response ( 2.1 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start Evamist therapy with one spray of Evamist per day. Make dosage adjustment based on the clinical response. Prime the Evamist container by spraying 5 sprays with the cover on before applying the first dose from a new applicator. Hold the container upright and vertical for spraying. Apply one, two or three sprays each morning to adjacent, non-overlapping areas on the inner surface of the forearm, starting near the elbow. Allow the sprays to dry for approximately 2 minutes before covering the site with clothing. Do not wash the application site for at least one hour. Application of Evamist to other skin surfaces has not been adequately studied. Evamist should not be applied to skin surfaces other than the forearm. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to estradiol from Evamist-treated skin. Cover the Evamist application site with clothing if another person may come into contact with that area of skin after the spray dries. Additional precautions to minimize unintentional secondary exposure are outlined in Patient Counseling Information [see Patient Counseling Information] and in the Patient Information Leaflet at the end of the prescribing information.

5 WARNINGS AND PRECAUTIONS • Estrogens increase the risk of gallbladder disease ( 5.5 ) • Discontinue estrogens if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.6 , 5.7 , 5.10 , 5.11 ) • Monitor thyroid function in women on thyroid hormone replacement therapy ( 5.12 , 5.21 ) 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. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued. 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 ( 14.2 )] . 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 daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 strokes per 10,000 women-years, respectively) [see Clinical Studies ( 14.2 )] . 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 non-fatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies ( 14.2 )] . Subgroup analysis of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) of CHD events in those women receiving daily CE (0.635 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) of 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 ( 14.2 )] . 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 and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of the original HERS, HERS II. Average follow-up in HERS II was an ad…

4 CONTRAINDICATIONS Evamist 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 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, angioedema, or hypersensitivity to Evamist. • 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 history of these conditions ( 4 , 5.1 ) • Active arterial thromboembolic disease (for example, stroke and MI), or history of these conditions ( 4 , 5.1 ) • Known anaphylactic reaction, angioedema, or hypersensitivity to Evamist ( 4 ) • 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 inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7.1 )

8.1 Pregnancy Risk Summary Evamist is not indicated for use in pregnancy. There are no data with the use of Evamist 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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the 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 (≥ 5 percent) with Evamist are: headache, breast tenderness and nipple pain, nausea, back pain, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 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 clinical practice. In a 12-week, randomized, placebo-controlled trial of Evamist in 454 women, 80 to 90 percent of women randomized to active drug received at least 70 days of therapy and 75 to 85 percent randomized to placebo received at least 70 days of therapy. The adverse reactions that occurred in at least 5 percent of women in any treatment group are shown in Table 1. Table 1. Frequency of Adverse Reactions (≥5%) in Any Treatment Group in a Controlled Study of Evamist Frequency n (%) System Organ Class Preferred Term 1 Spray 2 Sprays 3 Sprays Placebo (N = 77) Evamist (N = 76) Placebo (N = 76) Evamist (N = 74) Placebo (N = 75) Evamist (N = 76) Reproductive System and Breast Disorders Breast tenderness 0 (0) 4 (5) 4 (5) 5 (7) 0 (0) 4 (5) Nipple pain 0 (0) 2 (3) 0 (0) 5 (7) 0 (0) 1 (1) Gastrointestinal Disorders Nausea 5 (7) 1 (1) 1 (1) 2 (3) 4 (5) 2 (3) Infections and Infestations Nasopharyngitis 1 (1) 4 (5) 2 (3) 3 (4) 1 (1) 1 (1) Musculoskeletal and Connective Tissue Disorders Back pain 1 (1) 2 (3) 2 (3) 4 (5) 1 (1) 2 (3) Arthralgia 1 (1) 1 (1) 4 (5) 1 (1) 0 (0) 3 (4) Nervous system Headache 4 (5) 7 (9) 5 (7) 9 (12) 7 (9) 8 (11) Application site reactions were reported in 3 out of 226 (1.3%) women treated with Evamist. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Evamist. 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. Breasts: Breast swelling, breast mass, breast enlargement Cardiovascular: Heart rate increased Central nervous system: Dizziness, dysgeusia, paresthesia, lethargy, hypoesthesia Eyes: Eye irritation, ocular hyperemia Gastrointestinal: Abdominal pain, diarrhea, constipation, abdominal distension, dry mouth, decreased appetite Genitourinary system: Vaginal bleeding Musculoskeletal: Muscle spasms, arthritis Psychiatric: Insomnia, mood swings, anxiety, irritability, mood altered, depression Respiratory tract: Cough, dyspnea, dry throat Skin: Nipple and areola discoloration, usually on the same side of the body as the inner forearm on which Evamist is applied, rash, pruritus, alopecia, urticaria, dry skin, skin discoloration, chloasma Miscellaneous: Weight increased, malaise, fatigue, asthenia