Yuvafem

1 INDICATIONS AND USAGE Yuvafem are an estrogen (estradiol) indicated for the treatment of atrophic vaginitis due to menopause (1.1) 1.1 Treatment of Atrophic Vaginitis due to Menopause .

2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see Warnings and Precautions (5.3, 5.15) ] . 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 re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. Yuvafem should be administered intravaginally: 1 insert daily for 2 weeks, followed by 1 insert twice weekly (for example, Tuesday and Friday) (2.1) 2.1 Treatment of Atrophic Vaginitis due to Menopause Yuvafem should be administered intravaginally using the supplied applicator: 1 insert daily for 2 weeks, followed by 1 insert twice weekly (for example, Tuesday and Friday). Generally, women should be started at the 10 mcg dosage strength.

5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gallbladder disease (5.5) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.6, 5.7, 5.10, 5.11) The Yuvafem applicator may cause vaginal abrasion (5.17) Monitor thyroid function in women on thyroid replacement therapy (5.12, 5.19) 5.1 Risks from Systemic Absorption Yuvafem are intended only for vaginal administration. Systemic absorption occurs with the use of Yuvafem. The warnings, precautions and adverse reactions associated with the use of systemic estrogen-alone therapy should be taken into account. 5.2 Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. 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) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported 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 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.2) ] . Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. 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 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported 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 per 10,000 women-years) [see Clinical Studies (14.2) ] . The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.2) ] . Subgroup analysis of women 50 to 59 years of age suggests a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years). 1 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported 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 coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not d…

4 CONTRAINDICATIONS Yuvafem should not be used 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 myocardial infarction), or a history of these conditions Known anaphylactic reaction or angioedema to Yuvafem Known liver impairment or disease Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known or suspected pregnancy Undiagnosed abnormal genital bleeding (4) Known, suspected, or history of breast cancer (4, 5.3) Known or suspected estrogen-dependent neoplasia (4, 5.3) Active DVT, PE, or history of these conditions (4, 5.2) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions (4, 5.2) Known anaphylactic reaction or angioedema to Yuvafem Known liver impairment or disease (4, 5.11) Known protein C, protein S, or antithrombin deficient, or other known thrombophilic disorders (4) Known or suspected pregnancy (4, 8.1)

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted for Yuvafem. Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1) 7.1 Metabolic 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 side effects.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.2) ] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.3) ] In prospective, randomized, placebo-controlled, double-blind studies the most common adverse reactions (incidence ≥5 percent) were upper respiratory tract infection, headache, abdominal pain, back pain, genital pruritus, moniliasis, vulvovaginal mycotic infection and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 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. In a 12-month randomized, double-blind, parallel group, placebo-controlled study, a total of 309 postmenopausal women were randomized to receive either placebo or Yuvafem 10 mcg inserts. Adverse reactions with an incident of > 5 percent in the Yuvafem 10 mcg group and greater than those reported in the placebo group are listed in Table 1. Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of > 5 Percent in Women Receiving Yuvafem 10 mcg Body System Adverse Reaction Treatment Number (%) of Women Placebo N = 103 n = (%) Yuvafem N = 205 n (%) Body As A Whole Back Pain 2 (2) 14 (7) Digestive System Diarrhea 0 11 (5) Urogenital System Vulvovaginal Mycotic Infection 3 (3) 17 (8) Vulvavaginal Pruritus 2 (2) 16 (8) N = Total number of women in study. n = Number of women who experienced adverse reactions. In a 12-week, randomized, double-blind, placebo-controlled study, 138 postmenopausal women were randomized to receive either placebo or Yuvafem 10 mcg inserts. Adverse reactions with an incident of > 5 percent in the Yuvafem 25 mcg group and greater than those reported in the placebo group are listed in Table 2. Table 2: Treatment-Emergent Adverse Reactions Reported at a Frequency of > 5 Percent in Women Receiving Yuvafem 25 mcg Body System Adverse Reaction Treatment Number (%) of Women Placebo N = 47 N (%) Yuvafem N = 91 n (%) Body As A Whole Headache 3 (6) 8 (9) Abdominal Pain 2 (4) 6 (7) Back Pain 3 (6) 6 (7) Respiratory System Upper Respiratory Tract Infection 2 (4) 5 (5) Urogenital System Moniliasis Genital 1 (2) 5 (5) N = Total number of women in study. n = Number of women who experienced adverse reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Yuvafem 25 mcg. 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 Endometrial cancer, endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration Breast Breast cancer Cardiovascular Deep vein thrombosis Gastrointestinal Diarrhea Skin Urticaria, erythematous or pruritic rash, genital pruritus Central Nervous System Aggravated migraine, depression, insomnia Miscellaneous Fluid retention, weight increase, drug ineffectiveness, hypersensitivity, blood estrogen increase Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.