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 .

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.

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)

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 • ½ H 2 O with a molecular weight of 281.4. The structural formula is: 9ec90e26-figure-01

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.

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.

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.

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for Yuvafem. 12.3 Pharmacokinetics Absorption Estrogen drug products are well absorbed through the skin, mucous membranes and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism. In a single-center, randomized, open-label, multiple-dose, parallel group study conducted in 58 patients, Yuvafem 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL and 11.59 pg/mL, respectively after 12 weeks of treatment (see Table 3). Table 3: Arithmetic Means of Estradiol (E2), Estron (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Yuvafem 10 mcg Uncorrected for baseline, N=29 E2 E1 E1S AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93 53.57 Day 14 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48 50.07 Day 83 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53 49.76 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks. b CV: Coefficient of Variance for both AUC 0-24 and C ave (0-24) Table 4: Arithmetic Means of Estradiol (E2), Estron (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Yuvafem 10 mcg Uncorrected for baseline, N=29 E2 E1 E1S AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b AUC 0-24 (h.pg/mL) C ave (0-24) (pg/mL) %CV b Day1 495.27 20.64 25.70 567.07 23.63 28.96 5738.32 239.10 47.72 Day 14 466.63 19.44 33.53 662.94 27.62 24.36 7725.90 321.91 43.67 Day 83 278.27 11.59 61.83 500.06 20.84 34.99 4110.84 171.29 51.38 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks b CV: Coefficient of Variance for both AUC 0-24 and C ave (0-24) c N=28 for treatment before Day 14 and N=27 for treatments from Day 14. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

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

Yuvafem Estradiol STARCH, CORN HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE ESTRADIOL ESTRADIOL POLYETHYLENE GLYCOL, UNSPECIFIED off-white AN;276

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.

ANDA205256

Yuvafem

Estradiol

42291-962

HUMAN PRESCRIPTION DRUG

VAGINAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL AvKARE NDC 42291- 962 -18 Yuvafem® (estradiol vaginal inserts, USP) 10 mcg 3 Blister packs each containing 6 vaginal inserts (with disposable applicators) 18 Vaginal Inserts (with disposable applicators) Rx only Contents: 18 vaginal inserts with disposable applicators. Each insert contains: estradiol, USP 10 mcg; corn starch, hypromellose, lactose monohydrate and magnesium stearate. The film coating contains hypromellose and polyethylene glycol. Dosage: One (1) Yuvafem insert inserted vaginally once per day for two weeks, then one (1) insert inserted twice weekly (for example, Tuesday and Friday). Each insert is contained in a disposable single-use applicator. Please read the Patient Package Insert for complete product information. Dispenser: This carton contains information intended for the patient. This information is to be provided to the patient with each package dispensed. Keep out of reach of children. This package is not child-resistant. Store at 20° to 25° (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [ see USP Controlled Room Temperature]. Do not refrigerate. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 03-2018-05 AV 03/18 N3 42291 96218 7 Label Label 2

• Warnings and Precautions, Malignant Neoplasms (5.3) 11/2017

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling . 17.1 Vaginal Bleeding Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.3) ] . 17.2 Possible Serious Adverse Reactions with Estrogen-Alone therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms and Probable Dementia [see Warnings and Precautions (5.2, 5.3, 5.4) ] . 17.3 Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting. 17.4 Instructions for Use of Applicator Step 1: Tear off a single applicator. Step 2: Separate the plastic wrap and remove the applicator from the plastic wrap as shown in Figure A. If after opening the package you see that the insert has come out of the applicator but has not fallen out of the package, carefully put it back into the applicator for insertion. Please keep your hands clean and dry while handling the insert . Figure A Step 3: Hold the applicator so that the finger of one hand can press the applicator plunger as shown in Figure B. Figure B Step 4: Next select the best position for vaginal insertion of Yuvafem that is most comfortable for you. See suggested reclining Figure C or standing Figure D position illustrated below: Figure C Figure D Step 5: Using the other hand, guide the applicator gently and comfortably through the vaginal opening (see Figures C and D above). If prior to insertion the insert falls out of the applicator, throw the insert and applicator away and use a new insert-filled applicator . Step 6: The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less. Step 7: Once the insert-filled applicator has been inserted, gently press the plunger until the plunger is fully depressed. This will eject the insert inside your vagina where it will dissolve slowly over several hours. Step 8: After depressing the plunger, gently remove the applicator and dispose of it the same way you would a plastic tampon applicator. The applicator is of no further use and should be discarded properly. Insertion may be done at any time of the day. It is advisable to use the same time daily for all applications of Yuvafem (estradiol vaginal insert). If you have any questions, please consult your healthcare provider or pharmacist. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 YUVAFEM is a registered trademark of Amneal Pharmaceuticals LLC Mfg. Rev. 11-2017-03 AV 11/17 9ec90e26-figure-02 9ec90e26-figure-03 9ec90e26-figure-04 9ec90e26-figure-05

14 CLINICAL STUDIES 14.1 Effects on Atrophic Vaginitis Yuvafem 10 mcg A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of Yuvafem 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean 57.6 years of age) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse). Women inserted one insert intravaginally each day for 14 days, then one insert twice weekly for the remaining 50 weeks. The majority (92.9 percent) of the women were Caucasian (n=287), 3.2 percent were Black (n=10), 1.6 percent were Asian (n=5) and 2.2 percent were Other (n=7). All subjects were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH. Relief of Vaginal Symptoms Yuvafem 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 5). Table 5: Mean Change from Baseline to Week 12 in a Composite Score of Most Bothersome Symptoms Compared to Placebo – ITT Population a Placebo Yuvafem 10 mcg ITT Population a N 93 190 Baseline mean composite score 2.29 2.35 Change from baseline at Week 12 (LOCF) -0.84 -1.20 p-value versus Placebo --- 0.002 a All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation. Also demonstrated for Yuvafem 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p<0.001), a statistically significant decrease in parabasal cells at Week 12 (-37 percent compared to -9.3 percent for matching placebo, p<0.001), and a statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p<0.001). Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 subjects in the Yuvafem 10 mcg group who had a biopsy performed at end of study, 92 subjects had endometrial tissue that was atrophic or inactive and 73 subjects had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia. Three subjects exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation. Endometrial safety of Yuvafem 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 subjects who had a biopsy performed at end of study, 183 subjects had endometrial tissue that was atrophic or inactive and 111 subjects had no tissue or tissue insufficient for diagnosis. There was one case of complex hyperplasia without atypia. Two subjects exhibited polyps. Yuvafem 25 mcg A placebo-controlled comparison study was done in the U.S., in which 230 women were randomized to receive either placebo, Yuvafem 25 mcg or 10 mcg estradiol vaginal inserts. Women inserted one insert intravaginally each day for 14 days, then one insert twice weekly for the remaining 10 weeks. All subjects were assessed for vaginal symptoms. Yuvafem 25 mcg was superior to placebo in reducing the severity of a composite score of symptoms associated with atrophic vaginitis (see Table 6). An open-label, controlled comparison study was done in Canada in which 159 women were randomized to receive either Yuvafem 25 mcg or a comparator drug. Two (2) grams of the comparator drug was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks; Yuvafem 25 mcg was administered daily for 2 weeks, then twice weekly for the remaining 22 weeks. In this study, subjects were assessed for relief of symptoms. Yuvafem 25 mcg was equally effective as the approved comparator product at the 2 gm dose in the relief of symptoms. Table 6: Mean Change from Baseline to Week 7 and Week 12 in a Composite Score of Symptoms Compared to Placebo – ITT Population a Placebo Yuvafem 25 mcg ITT Population a N 47 91 Baseline mean 1.93 1.85 Change from baseline at Week 7 (LOCF) -0.85 -1.22 Change from baseline at Week 12 (LOCF) -0.83 -1.33 p-value versus Placebo – Week 7 (LOCF) --- 0.016 p-value versus Placebo – Week 12 (LOCF) --- 0.005 a All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation. In the placebo-controlled study endometrial biopsies in non-hysterectomized women at week 12 were performed on 86 subjects (Yuvafem 25 mcg: 32 subjects, estradiol 10 mcg: 33 subjects, Placebo: 21 subjects). Of these, 3 subjects each from the Yuvafem 25 mcg and placebo groups and 8 from the 10 mcg estradiol group had insufficient tissue samples. Among those with biopsies that yielded sufficient tissue, results were normal with the exception of one subject in the Yuvafem 25 mcg group, who had a simple hyperplasia without atypia. In the open-label study comparing Yuvafem 25 mcg with a comparator vaginal cream on 49 women in each treatment group, endometrial biopsies were obtained at the screening visit and at the end of treatment. At the end of the study (Week 24), all subjects in the Yuvafem treatment group whose biopsies yielded sufficient tissue showed an atrophic endometrium with the exception of one subject who had a proliferative endometrium. 14.2 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 7. Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI a Event Relative Risk CE vs. Placebo (95% nCIb) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c 0.95 (0.78 to 1.16) 54 57 Non-fatal MI c 0.91 (0.73 to 1.14) 40 43 CHD death c 1.01 (0.71 to 1.43) 16 16 All Strokes c 1.33 (1.05 to 1.68) 45 33 Ischemic stroke c 1.55 (1.19 to 2.01) 38 25 Deep vein thrombosis c,d 1.47 (1.06 to 2.06) 23 15 Pulmonary embolism c 1.37 (0.90 to 2.07) 14 10 Invasive breast cancer c 0.80 (0.62 to 1.04) 28 34 Colorectal cancer e 1.08 (0.75 to 1.55) 17 16 Hip fracture c 0.65 (0.45 to 0.94) 12 19 Vertebral fractures c,d 0.64 (0.44 to 0.93) 11 18 Lower arm/wrist fractures c,d 0.58 (0.47 to 0.72) 35 59 Total fractures c,d 0.71 (0.64 to 0.80) 144 197 Death due to other causes e,f 1.08 (0.88 to 1.32) 53 50 Overall mortality c,d 1.04 (0.88 to 1.22) 79 75 Global Index g 1.02 (0.92 to 1.13) 206 201 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index”. e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined. 10 Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [ hazard ratio (HR) 0.63 (95 percent CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)] . WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 8. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 8: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b Event Relative Risk CE/MPA vs Placebo (95% nCI c ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years Non-fatal MI 1.28 (1 to 1.63) 31 25 CHD death 1.10 (0.70 to 1.75) 8 8 All Strokes 1.31 (1.03 to 1.68) 33 25 Ischemic stroke 1.44 (1.09 to 1.90) 26 18 Deep vein thrombosis d 1.95 (1.43 to 2.67) 26 13 Pulmonary embolism 2.13 (1.45 to 3.11) 18 8 Invasive breast cancer e 1.24 (1.01 to 1.54) 41 33 Colorectal cancer 0.61 (0.42 to 0.87) 10 16 Endometrial cancer d 0.81 (0.48 to 1.36) 6 7 Cervical cancer d 1.44 (0.47 to 4.42) 2 1 Hip fracture 0.67 (0.47 to 0.96) 11 16 Vertebral fractures d 0.65 (0.46 to 0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59 to 0.85) 44 62 Total fractures d 0.76 (0.69 to 0.83) 152 199 Overall Mortality f 1 (0.83 to 1.19) 52 52 Global Index g 1.13 (1.02 to 1.25) 184 165 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 5059 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44 to 1.07)] . 14.3 Women’s Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominately healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5) ] . The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5) ] . When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5)] .

15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA . 2007; 297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med . 2006; 166:357-365. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med . 2006; 166:772-780. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA . 2004; 292:1573-1580. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA . 2006; 295:1647-1657. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA . 2003; 289:3234-3253. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic cancers and Associated Diagnostic Procedures. JAMA . 2003; 290:1739-1748. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA . 2004; 291:2947-2958. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women’s Health Initiative Randomized Trial. J Bone Miner Res . 2006; 21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative. Circulation . 2006; 113:2425-2434.

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.

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 42291-962-08 18 applicators: NDC 42291-962-18 Keep out of reach of children 16.2 Storage and Handling Store at 20º to 25ºC (68º to 77ºF), excursions permitted to 15º to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature]. Do not refrigerate.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.3) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2, 5.4) and Clinical Studies (14.2, 14.3) ] . The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.2) and Clinical Studies (14.2) ] . The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) , Use in Specific Populations (8.5) and Clinical Studies (14.3) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2, 5.4) and Clinical Studies (14.2, 14.3) ] . The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.2) and Clinical Studies (14.2) ] . The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) , Use in Specific Populations (8.5) and Clinical Studies (14.3) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.3) and Clinical Studies (14.2) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA See full prescribing information for complete boxed warning. Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.3) Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.4) The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) (5.2) The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4) Estrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.4) The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE) and myocardial infarction (MI) (5.2) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.3) The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4)