Femring

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) ]. Most common adverse reactions (incidence > 5 percent) are vaginal bleeding and breast tenderness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, Millicent at 1-877-810-2101 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 13-week clinical trial that included 225 postmenopausal women treated with Femring and 108 women treated with placebo vaginal rings, adverse reactions that occurred at a rate of ≥ 2 percent are summarized in Table 1 . Table 1. Incidence of Adverse Reactions Occurring in ≥ 2 Percent of Subjects Presented in Descending Frequency of Preferred Term Adverse Event Placebo (n = 108) Estradiol 0.05 mg/day (n = 113) Estradiol 0.10 mg/day (n = 112) n (percent) n (percent) n (percent) Headache (NOS) 10 (9.3) 8 (7.1) 11 (9.8) Intermenstrual Bleeding 2 (1.9) 9 (8.0) 11 (9.8) Vaginal Candidiasis 3 (2.8) 7 (6.2) 12 (10.7) Breast Tenderness 2 (1.9) 7 (6.2) 12 (10.7) Back Pain 4 (3.7) 7 (6.2) 4 (3.6) Abdominal Distension 3 (2.8) 8 (7.1) 3 (2.7) Sinusitis (NOS) 2 (1.9) 2 (1.8) 4 (3.6) Uterine Pain 1 (0.9) 2 (1.8) 5 (4.5) Urinary Tract Infection (NOS) 2 (1.9) 1 (0.9) 4 (3.6) AE = adverse event; NOS = not otherwise specified 6.2 Postmarketing Experience A few cases of toxic shock syndrome (TSS) have been reported in women using vaginal rings. TSS is a rare, but serious disease that may cause death. Warning signs of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-rash on face and body. Cases of ring adherence to the vaginal or bladder wall, making ring removal difficult, have been reported in women using vaginal rings and may require surgical removal of the device. Women should be carefully evaluated for vaginal or bladder wall ulceration or erosion. Cases of vaginal erosion and vaginal ulceration have been reported with other estradiol vaginal rings. If an ulceration or erosion has occurred, consideration should be given to leaving the ring out and not replacing it until healing is complete to prevent the ring from adhering to the vaginal tissue. A few cases of bowel obstruction associated with vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated. A few cases of inadvertent ring insertion into the urinary bladder, which may require surgical removal, have been reported for women using vaginal rings. Persistent unexplained urinary symptoms should be carefully evaluated. The following additional adverse reactions have been identified during post-approval use of Femring. 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 Uterine cancer, vaginal hemorrhage, ovarian cyst, irregular menstruation, metrorrhagia, menorrhagia, dysmenorrhea, uterine enlargement. Breasts Breast cancer, fibrocystic breast disease, breast disorder, breast mass, breast enlargement, breast pain, nipple pain, breast discharge. Cardiovascular Chest pain, increased blood pressure, irregular heart rate, pulmonary embolism, cerebrovascular accident (stroke), hemiparesis, transient ischemic attack, thrombosis. Gastrointestinal Abdominal pain, pancreatitis, cholecystitis, cholelithiasis, vomiting. Skin Generalized erythema, erythema multiforme, erythema nodosum, rash, hirsutism, pruritis. Eyes Blindness, contact lens intolerance. Central Nervous System Dizziness, headache, depression, nervousness, mood disturbances, irritability. Miscellaneous Medical device complication, back pain, angioedema, weight increased/decreased, edema, libido increased/decreased, urticaria, hypersensitivity, anaphylaxis.

4 CONTRAINDICATIONS Femring is contraindicated 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 MI), or a history of these conditions Known anaphylactic reaction or angioedema to Femring 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 , 5.2 ) Known or suspected 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 a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction or angioedema to Femring ( 4 ) Known liver impairment or disease ( 4 , 5.10 ) Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) Known or suspected pregnancy ( 4 , 8.1 )

11 D ESCRIPTION Femring (estradiol acetate vaginal ring) is an off-white, soft, flexible ring with a central core containing estradiol acetate. Femring is made of cured silicone elastomer composed of dimethyl polysiloxane silanol, silica (diatomaceous earth), normal propyl orthosilicate, stannous octoate; barium sulfate and estradiol acetate. The rings have the following dimensions: outer diameter 56 mm, cross-sectional diameter 7.6 mm, core diameter 2 mm. Femring is available in two strengths: Femring 0.05 mg/day has a central core that contains 12.4 mg of estradiol acetate, which releases at a rate equivalent to 0.05 mg of estradiol per day for 3 months. Femring 0.10 mg/day has a central core that contains 24.8 mg of estradiol acetate, which releases at a rate equivalent to 0.10 mg of estradiol per day for 3 months. Estradiol acetate is chemically described as estra-1,3,5(10)-triene-3,17β-diol-3-acetate. The molecular formula of estradiol acetate is C 20 H 26 O 3 and the molecular weight of estradiol acetate is 314.42. The Structural formula of Estradiol acetate is chemically described as estra-1,3,5(10)-triene-3,17b-diol-3-acetate

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 [ s ee Warnings and Precautions ( 5.2 , 5.14 )] . 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. One ring inserted into the vagina for 3 months. Patients should be started at the lowest dose. ( 2.1 , 2.2 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with 0.05 mg/day. Dosage adjustment should be guided by the clinical response. Therapy should be started at the lowest effective dose and the shortest duration consistent with treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals. 2.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause. Start therapy with 0.05 mg/day. Dosage adjustment should be guided by the clinical response. Therapy should be started at the lowest effective dose and the shortest duration consistent with treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals.

1 INDICATIONS AND USAGE Femring is an estrogen indicated for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause. 1.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause.

10 OVERDOSAGE Overdosage of estrogen may cause nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Femring with institution of appropriate symptomatic care.

7 DRUG INTERACTIONS No drug interaction studies have been conducted for Femring. Inducers and/or 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 decrease the plasma concentration 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 the plasma concentration 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, which is 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 There are no pharmacodynamic data for Femring. 1 2.3 Pharmacokinetics Absorption Estradiol acetate is hydrolyzed to estradiol which is absorbed through the vaginal mucosa as evidenced by the mean time to maximum concentration (t max ) for estradiol of about 1 hour (range 0.25 to 1.5 hrs). After achieving the Cmax the estradiol concentration starts declining during the first 24 to 48 hours and then at a relatively constant rate for the remainder of the 3-month dosing interval (see Figure 1 for results from rings stored for 16 months). In vitro studies have shown that this initial release is higher as the rings age upon storage. Following administration of Femring (0.05 mg/day estradiol), average serum estradiol concentration was 40.6 pg/mL; the corresponding apparent in vivo estradiol delivery rate was 0.052 mg/day. Following administration of Femring (0.10 mg/day estradiol), average serum estradiol concentration was 76 pg/mL; apparent in vivo delivery rate was 0.097 mg/day. Results are summarized in Table 2 below. Table 2. Summary of Mean (Percent RSD)* Pharmacokinetic Parameters for Femring Dose (as estradiol) Number of subjects C max (pg/mL) T max (hour) C avg (pg/mL) 0.05 mg/day Estradiol 1 25 1129 (25) 0.9 (41) 40.6 (26) Estrone 1 25 141 (25) 6.2 (84) 35.9 (21) Estrone sulfate 1 25 2365 (44) 9.3 (39) 494.6 (48) 0.10 mg/day Estradiol 2 12 1665 (23) 0.7 (90) -- 4 Estradiol 3 11 -- -- 76.0 (24) Estrone 3 11 -- -- 45.7 (25) * Relative Standard Deviation, 1 Study 1, 2 Study 2, 3 Study 3, 4 -- Not determined Consistent with the avoidance of first pass metabolism achieved by vaginal estradiol administration, serum estradiol concentrations were slightly higher than estrone concentrations. 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 a 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 intestine followed by reabsorption. In postmenopausal women, a significant proportion 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. The estradiol apparent elimination half-life value is 21 to 26 hours. Use in Specific Populations No pharmacokinetic studies were conducted with Femring in specific populations, including women with renal or hepatic impairment. Figure 1. Mean serum estradiol concentrations following multiple dose administration of Femring (0.05 mg/day estradiol) (second dose administered at 13 weeks) (inset: mean (±SD) of serum concentrati

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, which is 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 There are no pharmacodynamic data for Femring.

1 2.3 Pharmacokinetics Absorption Estradiol acetate is hydrolyzed to estradiol which is absorbed through the vaginal mucosa as evidenced by the mean time to maximum concentration (t max ) for estradiol of about 1 hour (range 0.25 to 1.5 hrs). After achieving the Cmax the estradiol concentration starts declining during the first 24 to 48 hours and then at a relatively constant rate for the remainder of the 3-month dosing interval (see Figure 1 for results from rings stored for 16 months). In vitro studies have shown that this initial release is higher as the rings age upon storage. Following administration of Femring (0.05 mg/day estradiol), average serum estradiol concentration was 40.6 pg/mL; the corresponding apparent in vivo estradiol delivery rate was 0.052 mg/day. Following administration of Femring (0.10 mg/day estradiol), average serum estradiol concentration was 76 pg/mL; apparent in vivo delivery rate was 0.097 mg/day. Results are summarized in Table 2 below. Table 2. Summary of Mean (Percent RSD)* Pharmacokinetic Parameters for Femring Dose (as estradiol) Number of subjects C max (pg/mL) T max (hour) C avg (pg/mL) 0.05 mg/day Estradiol 1 25 1129 (25) 0.9 (41) 40.6 (26) Estrone 1 25 141 (25) 6.2 (84) 35.9 (21) Estrone sulfate 1 25 2365 (44) 9.3 (39) 494.6 (48) 0.10 mg/day Estradiol 2 12 1665 (23) 0.7 (90) -- 4 Estradiol 3 11 -- -- 76.0 (24) Estrone 3 11 -- -- 45.7 (25) * Relative Standard Deviation, 1 Study 1, 2 Study 2, 3 Study 3, 4 -- Not determined Consistent with the avoidance of first pass metabolism achieved by vaginal estradiol administration, serum estradiol concentrations were slightly higher than estrone concentrations. 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 a 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 intestine followed by reabsorption. In postmenopausal women, a significant proportion 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. The estradiol apparent elimination half-life value is 21 to 26 hours. Use in Specific Populations No pharmacokinetic studies were conducted with Femring in specific populations, including women with renal or hepatic impairment. Figure 1. Mean serum estradiol concentrations following multiple dose administration of Femring (0.05 mg/day estradiol) (second dose administered at 13 weeks) (inset: mean (±SD) of serum concentrati

20230101

5

3 DOSAGE FORMS AND STRENGTHS The following two strengths of Femring are available: Femring (0.05 mg/day): Each off-white, soft, flexible ring has a central core that contains 12.4 mg of estradiol acetate, which releases at a rate equivalent to 0.05 mg of estradiol per day for 3 months. Femring (0.10 mg/day): Each off-white, soft, flexible ring has a central core that contains 24.8 mg of estradiol acetate, which releases at a rate equivalent to 0.10 mg of estradiol per day for 3 months. Femring (0.05 mg/day): Each off-white, soft, flexible ring has a central core that contains 12.4 mg of estradiol acetate, which releases at a rate equivalent to 0.05 mg of estradiol per day for 3 months. ( 3 ) Femring (0.10 mg/day): Each off-white, soft, flexible ring has a central core that contains 24.8 mg of estradiol acetate, which releases at a rate equivalent to 0.10 mg of estradiol per day for 3 months. ( 3 )

Femring estradiol acetate DIMETHICONE DIATOMACEOUS EARTH STANNOUS 2-ETHYLHEXANOATE TETRAPROPYL ORTHOSILICATE BARIUM SULFATE ESTRADIOL ACETATE ESTRADIOL Femring estradiol acetate DIATOMACEOUS EARTH STANNOUS 2-ETHYLHEXANOATE TETRAPROPYL ORTHOSILICATE BARIUM SULFATE ESTRADIOL ACETATE ESTRADIOL DIMETHICONE

13.1 Carcinogenesis, Mutagenesis, 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. Estradiol acetate was assayed for mutation in four histidine-requiring strains of Salmonella typhimurium and in one tryptophan-requiring strain of Escherichia coli . Estradiol acetate did not induce mutations in any of the bacterial strains tested under the conditions employed.

13 NONCLIN I CAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, 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. Estradiol acetate was assayed for mutation in four histidine-requiring strains of Salmonella typhimurium and in one tryptophan-requiring strain of Escherichia coli . Estradiol acetate did not induce mutations in any of the bacterial strains tested under the conditions employed.

NDA021367

Femring

estradiol acetate

72495-202

HUMAN PRESCRIPTION DRUG

VAGINAL

5.1 7 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe vulvar and vaginal atrophy due to menopause.

NDC 72495-201-05 Femring® (estradiol acetate vaginal ring) 0.05 mg/day Rx only label

Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 11/2017

Manufactured by Millicent Pharma (NI) Limited for Millicent U.S., Inc, East Hanover, NJ 07936 Product of Germany. To report SUSPECTED ADVERSE REACTIONS, contact Millicent at 1-877-810-2101 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. FEMRING® is a registered trademark of Millicent Pharma Limited ©2018 Millicent. All rights reserved.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information and Instructions for Use ). 17.1 Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [ see Warnings and Precautions (5.2) ] . 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 ( 5.1 , 5.2 , 5.3 )] . 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. Contact with blood may cause discoloration of Femring during use. This does not affect the release of the drug. Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible.

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms A 13-week double-blind, placebo-controlled clinical trial was conducted to evaluate the efficacy of 2 doses of the vaginal ring in the treatment of moderate to severe vasomotor symptoms in 333 postmenopausal women between 29 and 85 years of age (mean age 51.7 years, 77 percent were Caucasian) who had at least 7 moderate to severe hot flushes daily or at least 56 moderate to severe hot flushes per week before randomization. Patients were randomized to receive either placebo, Femring 0.05 mg/day or Femring 0.10 mg/day. Femring 0.05 mg/day and Femring 0.10 mg/day were shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Frequency results are shown in Table 3 . Severity results are shown in Table 4 . Table 3. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF Visit Placebo (n = 105) Estradiol 0.05 mg/day (n = 111) Estradiol 0.10 mg/day (n = 109) Baseline [1] Mean (SD) 83.62 (60.42) 73.83 (24.53) 75.11 (25.44) Week 4 Mean (SD) 51.14 (51.19) 21.59* (27.76) 11.37* (19.43) Mean Change from Baseline (SD) -32.48 (46.25) -52.24* (32.92) -63.75* (26.68) p value vs. Placebo (95 percent CI) [2] - <0.001 (-30.7, -8.8) <0.001 (-42.2, -20.3) Week 12 Mean (SD) 42.21 (41.13) 15.48* (25.42) 8.25* (16.58) Mean Change from Baseline (SD) -41.41 (65.61) -58.36* (31.36) -66.87* (27.44) p value vs. Placebo (95 percent CI) [2] - 0.006 (-30.5, -3.4) <0.001 (-39.1, -11.8) *Denotes statistical significance at the 0.050 level. [1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two weeks between screening and randomization. [2] p values and confidence intervals are from a two-way ANOVA with factors for treatment and study center for the difference between treatment groups in the mean change from baseline. Confidence intervals are adjusted for multiple comparisons within each timepoint using Dunnett’s method. ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval Table 4. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF Visit Placebo (n = 105) Estradiol 0.05 mg/day (n = 111) Estradiol 0.10 mg/day (n = 109) Baseline [1] Mean (SD) 2.51 (0.26) 2.46 (0.23) 2.48 (0.24) Week 4 Mean (SD) 2.23 (0.71) 1.67* (1.07) 1.15* (1.14) Mean Change from Baseline (SD) -0.28 (0.69) - 0.79* (1.08) -1.33* (1.10) p value vs. Placebo (95 percent CI) [2] - <0.001 (-0.8, -0.2) <0.001 (-1.3, -0.8) Week 12 Mean (SD) 2.00 (0.96) 1.41* (1.17) 0.92* (1.09) Mean Change from Baseline (SD) -0.51 (0.94) -1.06* (1.16) -1.56* (1.06) p value vs. Placebo (95 percent CI) [2] - <0.001 (-0.9, -0.2) <0.001 (-1.4, -0.7) *Denotes statistical significance at the 0.050 level. [1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the average severity of MSVS during the two weeks between screening and randomization. [2] p values and confidence intervals are from a two-way ANOVA with factors for treatment and study center for the difference between treatment groups in the mean change from baseline. Confidence intervals are adjusted for multiple comparisons within each timepoint using Dunnett’s method. ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 14.2 Effects on Vulvar and Vaginal Atrophy In the same 13-week clinical trial, vaginal superficial cells increased by a mean of 16.0 percent and 18.9 percent for Femring 0.05 mg/day and Femring 0.10 mg/day, respectively, as compared to 1.11 percent for placebo at week 13. A corresponding reduction in parabasal cells was observed at week 13. Vaginal pH decreased for Femring 0.05 mg/day and Femring 0.10 mg/day by a mean of 0.73 and 0.60, respectively, compared to a mean decrease of 0.25 in the placebo group. 14.3 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 cause. 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 5 . Table 5. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI a Event Relative Risk CE vs. Placebo (95 percent nCI b ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c 0.95 (0.78-1.16) 54 57 Non-fatal MI c 0.91 (0.73 - 1.14) 40 43 CHD death c 1.01 (0.71 - 1.43) 16 16 All strokes c 1.33 (1.05-1.68) 45 33 Ischemic stroke c 1.55 (1.19 - 2.01) 38 25 Deep vein thrombosis c,d 1.47 (1.06-2.06) 23 15 Pulmonary embolism c 1.37 (0.90-2.07) 14 10 Invasive breast cancer c 0.80 (0.62-1.04) 28 34 Colorectal cancer c 1.08 (0.75-1.55) 17 16 Hip fracture c 0.65 (0.45-0.94) 12 19 Vertebral fractures c,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures c,d 0.58 (0.47-0.72) 35 59 Total fractures c,d 0.71 (0.64-0.80) 144 197 Deaths due to other causes e,f 1.08 (0.88-1.32) 53 50 Overall Mortality c,d 1.04 (0.88-1.22) 79 75 Global Index g 1.02 (0.92-1.13) 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, PE, 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 were 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. See Table 5. 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 therapy increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined. 10 See Table 5. 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 , 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI , 0.46-1.11)] . 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 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 6 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 6. 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 CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00 - 1.63) 31 25 CHD death 1.10 (0.70 - 1.75) 8 8 All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09 - 1.90) 26 18 Deep vein thrombosis d 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer e 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer d 0.81 (0.48-1.36) 6 7 Cervical cancer d 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures d 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59-0.85) 44 62 Total fractures d 0.76 (0.69-0.83) 152 199 Overall Mortality c,f 1.00 (0.83-1.19) 52 52 Global Index g 1.13 (1.02-1.25) 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, PE, colorectal cancer, hip fracture, or death due to other causes. Timing of 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 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)] . 14.4 Women’s Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly 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, 0.83-2.66). 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 (5.3) , 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 of age, and 18 percent were 75 years of age and older) to evaluate the effects of 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, 1.21-3.48). 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 substudy 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 (5.3) , 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, 1.19-2.60). 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 (5.3) , 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.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Femring to determine whether those over 65 years of age differ from younger subjects in their response to Femring. 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 (5.3) , and Clinical Studies (14.4) ] . 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 (5.3) , and Clinical Studies (14.4) ] .

8.3 Nursing Mothers Femring 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-alone therapy. Caution should be exercised when Femring is administered to a nursing woman.

8.4 Pediatric Use Femring is not indicated in children. Clinical studies have not been conducted in the pediatric population.

8.1 Pregnancy Femring 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 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 ( 5.3 , 8.5 ) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised 08/2018 8.1 Pregnancy Femring 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 Femring 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-alone therapy. Caution should be exercised when Femring is administered to a nursing woman. 8.4 Pediatric Use Femring 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 Femring to determine whether those over 65 years of age differ from younger subjects in their response to Femring. 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 (5.3) , and Clinical Studies (14.4) ] . 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 (5.3) , and Clinical Studies (14.4) ] . 8.6 R enal Impairment The effect of renal impairment on the pharmacokinetics of Femring has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Femring has not been studied.

16 HOW SUPPLIED/STORAGE AND HANDLING 16. 1 How Supplied Each Femring (estradiol acetate vaginal ring) is individually packaged in a pouch consisting of one side medical grade paper and the other side polyester/polyethylene laminate. N 72495-201-05 Femring 0.05 mg/day (estradiol acetate vaginal ring) is available in single units. N 72495-202-10 Femring 0.10 mg/day (estradiol acetate vaginal ring) is available in single units. 16.2 Storage and Handling Store at 25º C (77º F); excursions permitted to 15 to 30º C (59 to 86º F) [see USP Controlled Room Temperature]. Do not store unpouched. Insert immediately upon removal from the protective pouch.

16.2 Storage and Handling Store at 25º C (77º F); excursions permitted to 15 to 30º C (59 to 86º F) [see USP Controlled Room Temperature]. Do not store unpouched. Insert immediately upon removal from the protective pouch.

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 (5.2) ] . Cardiovascular D isorders and P robable D ementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [ see Warnings and Precautions ( 5.1 , 5.3 ) , and Clinical Studies ( 14.3 , 14.4 ) ] . 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 (5.1) , and Clinical Studies (14.3) ]. The WHI Memory Study ( WHIMS ) estrogen-alone ancillary study of the 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 (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.4) ] . 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 ( 5.1 , 5.3 ) and Clinical Studies ( 14.3 , 14.4) ] . 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 (5.1) , and Clinical Studies (14.3) ] . The WHIMS estrogen plus progestin ancillary study of the WHI reported 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 (5.3) , Use in Specific Populations (8.5) and Clinical Studies (14.4) ] . 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 (14.3) ] . 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 ( 5.2 ) Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.1 ) 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 ( 5.3 ) Estrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer ( 5.2 ) 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 ( 5.3 )