Yuvafem

RECENT MAJOR CHANGES Warnings and Precautions, Malignant Neoplasms (5.3) 02/2024

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.

3 DOSAGE FORMS AND STRENGTHS Yuvafem are small, white, round, film-coated, bi-convex vaginal inserts containing 10 mcg of estradiol, USP. Each vaginal insert is 6 mm in diameter and is administered in a disposable applicator. Vaginal insert: One 10 mcg vaginal insert contains 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol, USP (3)

4 CONTRAINDICATIONS Yuvafem is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.3) ] . Breast cancer or a history of breast cancer [see Warnings and Precautions (5.3) ] . Estrogen-dependent neoplasia [see Warnings and Precautions (5.3) ] . Active DVT, PE, or history of these conditions [see Warnings and Precautions (5.2) ] . Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warnings and Precautions (5.2) ] . Known anaphylactic reaction, or angioedema, or hypersensitivity to Yuvafem [see Warnings and Precautions (5.16) ] . Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Undiagnosed abnormal genital bleeding (4 , 5.3) Breast cancer or a history of breast cancer (4 , 5.3) Estrogen-dependent neoplasia (4 , 5.3) Active DVT, PE, or history of these conditions (4 , 5.2) Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions (4 , 5.2) Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol (4 , 5.16) Hepatic impairment or disease (4 , 5.11) Protein C, protein S, or antithrombin deficient, or other known thrombophilic disorders (4)

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.

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.

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3) Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women’s Health Initiative Memory ancillary studies of the Women’s Health Initiative (8.5) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2017 8.1 Pregnancy Yuvafem should not be used during pregnancy [see Contraindications (4) ] . There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy. 8.3 Nursing Mothers Yuvafem should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when Yuvafem is administered to a nursing woman. 8.4 Pediatric Use Yuvafem is not indicated in children. 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 Yuvafem to determine whether those over 65 years of age differ from younger subjects in their response to Yuvafem. 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 (14.2) ] . 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 (14.2) ] . 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 (5.4) and Clinical Studies (14.3) ] . 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 (5.4) and Clinical Studies (14.3) ] . 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of Yuvafem has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Yuvafem has not been studied.

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 FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

11 DESCRIPTION Yuvafem (estradiol vaginal inserts), 10 mcg, are small, white, film-coated insertts containing 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol, USP. Each Yuvafem, 10 mcg contains the following excipients: corn starch, hypromellose, lactose monohydrate and magnesium stearate. The film coating contains hypromellose and polyethylene glycol. Each Yuvafem vaginal insert is 6 mm in diameter and is placed in a disposable applicator. Each insert-filled applicator is packaged separately in a blister pack. Yuvafem are used intravaginally. When the insert comes in contact with the vaginal mucosa, estradiol, USP is released into the vagina. USP Dissolution Test is pending. Estradiol hemihydrate is a white, almost white or colorless crystalline solid, chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The chemical formula is C 18 H 24 O 2 • 1⁄2 H 2 O with a molecular weight of 281.4. The structural formula is: 9ec90e26-figure-01

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 Yuvafem therapy with institution of appropriate symptomatic care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Yuvafem, 10 mcg , are supplied as white to off-white, round biconvex, film-coated unscored inserts debossed with “276” on obverse and “AN” on the reverse. Each Yuvafem, 10 mcg , is contained in a disposable, single-use applicator, packaged in a blister pack. Cartons contain 8 or 18 applicators with inset inserts. Yuvafem, 10 mcg 8 applicators: NDC 65162-226-21 18 applicators: NDC 65162-226-23 Keep out of reach of children. 16.2 Storage and Handling Store at 20o to 25oC (68o to 77oF); excursions permitted between 15o to 30oC (59o to 86oF) [see USP Controlled Room Temperature]. Do not refrigerate.