Femring

Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 11/2023

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.

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 (5.2 , 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.

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 )

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 )

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, contact 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 AE = adverse event; NOS = not otherwise specified 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) 6.2 Postmarketing Experience 1. 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. 2. 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. 3. A few cases of bowel obstruction associated with vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated. 4. 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, contac …

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.

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 ) 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 Renal 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.

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.

11 DESCRIPTION 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

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.

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 20o C to 25o C (68o F to 77o F); excursions permitted to -20o C to 40o C (-4o F to 104o F). Do not store unpouched. Insert immediately upon removal from the protective pouch.

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.