Estradiol

Warnings and Precautions, Malignant Neoplasms ( 5.3 ) 2/2024 Warnings and Precautions, Malignant Neoplasms ( 5.3 ) 2/2024

1 INDICATIONS AND USAGE Estradiol vaginal inserts are an estrogen indicated for the treatment of atrophic vaginitis due to menopause ( 1.1 ) 1.1 Treatment of Atrophic Vaginitis due to Menopause

2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women with a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.3 , 5.15 )] . Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. Administer estradiol vaginal inserts 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 Administer estradiol vaginal inserts intravaginally using the supplied applicator: 1 insert daily for 2 weeks, followed by 1 insert twice weekly (for example, Tuesday and Friday).

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

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

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions ( 5.2 )] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions ( 5.3 )] The most common adverse reactions (incidence ≥5 percent) with estradiol vaginal inserts are: back pain, vulvovaginal pruritus, vulvovaginal mycotic infection and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 estradiol 10 mcg vaginal inserts. Adverse reactions with an incidence of ≥5 percent in the estradiol 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 Estradiol 10 mcg Body System Adverse Reaction Treatment Number (%) of Women Placebo N = 103 n (%) Estradiol 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) Vulvovaginal Pruritus 2 (2) 16 (8) 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 estradiol 10 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. Gastrointestinal disorders Diarrhea General disorders and administration site conditions Drug ineffective Immune system disorders Hypersensitivity Investigations Blood estrogen increased Weight increased Metabolism and nutrition disorders Fluid retention Neoplasms benign and malignant Breast cancer Endometrial cancer Psychiatric disorders Depression Insomnia Central Nervous System Aggravated migraine Reproductive system and breast disorders Endometrial hyperplasia Vulvovaginal burning sensation Vulvovaginal pain Genital pruritus Vulvovaginal rash Vulvovaginal swelling Vaginismus Vaginal ulceration Skin and subcutaneous tissue disorders Rash Rash erythematous Rash pruritic Urticaria Vascular disorders Deep vein thrombosis

7 DRUG 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 adverse reactions. Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Estradiol vaginal inserts are not indicated for use in pregnancy. There are no data with the use of estradiol vaginal inserts in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol vaginal inserts and any potential adverse effects on the breastfed child from estradiol vaginal inserts or from the underlying maternal condition. 8.4 Pediatric Use Estradiol vaginal inserts are not indicated for use in pediatric patients. 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 estradiol vaginal inserts to determine whether those over 65 years of age differ from younger subjects in their response to estradiol vaginal inserts. 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 )] .

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

11 DESCRIPTION Estradiol vaginal inserts USP, 10 mcg are white to off-white, round, film-coated, unscored, biconvex inserts containing 10.3 mcg of estradiol hemihydrate, USP equivalent to 10 mcg of estradiol. Each 10 mcg estradiol vaginal insert contains the following excipients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, and polyethylene glycol. Each estradiol 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. Estradiol vaginal inserts are used intravaginally. When the insert comes in contact with the vaginal mucosa, estradiol is released into the vagina. Estradiol hemihydrate, USP is white to practically white crystals or powder and chemically described as estra1,3,5 (10)-triene-3,17β-diol, hydrate (2:1). The structural formula is: C 18 H 24 O 2 . 1/2 H 2 O M.W. 281.4 (Estradiol hemihydrate, USP) FDA approved dissolution test specifications differ from USP. Chemical structure

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 estradiol therapy with institution of appropriate symptomatic care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol vaginal inserts USP, 10 mcg, are white to off-white, round, film-coated, unscored, biconvex inserts, debossed with " TV " on one side and " T5 " on the other side. Each insert is contained in a disposable, single-use applicator, packaged in a blister pack. Cartons contain 8 or 18 applicators with inset inserts. Estradiol vaginal inserts USP, 10 mcg 8 applicators: NDC 0093-3223-08 18 applicators: NDC 0093-3223-97 Keep out of reach of children. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Do not refrigerate.

16.1 How Supplied Estradiol vaginal inserts USP, 10 mcg, are white to off-white, round, film-coated, unscored, biconvex inserts, debossed with " TV " on one side and " T5 " on the other side. Each insert is contained in a disposable, single-use applicator, packaged in a blister pack. Cartons contain 8 or 18 applicators with inset inserts. Estradiol vaginal inserts USP, 10 mcg 8 applicators: NDC 0093-3223-08 18 applicators: NDC 0093-3223-97 Keep out of reach of children.