Estradiol Acetate

FDA Drug Information • Also known as: Femring

Brand Names: Femring
Dosage Form: POWDER
Product Type: BULK INGREDIENT

⚠ Boxed Warning (Black Box)

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 (5.2) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 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 )

Description

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

What Is Estradiol Acetate Used For?

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.

Dosage and Administration

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.

Side Effects (Adverse Reactions)

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,...

Drug Interactions

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.

Contraindications

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 )

Pregnancy and Breastfeeding

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.

Overdosage

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.

How Supplied

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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.