Estradiol Gel

1 INDICATIONS AND USAGE Estradiol gel 0.1% is an estrogen indicated for the treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ). 1.1 Treatment of Moderate to Severe Vasomotor Symptoms 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 a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.14 )] . 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 whether treatment is still necessary. Daily administration of 0.25 to 1.25 grams of estradiol gel 0.1% to the right or left upper thigh on alternating days. Women should be started with the lowest effective dose and the dose should be evaluated periodically ( 2 ). 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with the 0.25 grams applied once daily on the skin of either the right or left upper thigh. Adjust the dose up to a maximum of 1.25 grams, as needed. The application surface area should be about 5 by 7 inches (approximately the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, apply estradiol gel 0.1% to the right or left upper thigh on alternating days. Do not apply estradiol gel 0.1% on the face, breasts, or irritated skin or in or around the vagina. Allow gel to dry after application before dressing. Do not wash the application site within 1 hour after applying estradiol gel 0.1%. Avoid contact of the gel with eyes. Wash hands after application.

3 DOSAGE FORMS AND STRENGTHS Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol respectively). Estradiol gel 0.1% is a clear, colorless gel, which is odorless when dry. Gel: 0.25, 0.5, 0.75, 1.0, and 1.25 gram-filled single-dose foil packets containing 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively ( 3 ).

4 CONTRAINDICATIONS Estradiol gel 0.1% is contraindicated in women with any of the following conditions: • Undiagnosed abnormal genital bleeding [see Warning and Precautions ( 5.2 )] • Breast cancer or history of breast cancer [see Warning and Precautions ( 5.2 )] • Estrogen-dependent neoplasia [see Warning and Precautions ( 5.2 )] • Active DVT, PE, or history of these conditions [see Warning and Precautions ( 5.1 )] • Active arterial thromboembolic disease (e.g., stroke and MI), or a history of these conditions [see Warning and Precautions ( 5.1 )] • Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel 0.1% • Hepatic impairment or disease • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders • Undiagnosed abnormal genital bleeding ( 4 ) • Breast cancer or a history of breast cancer ( 4 , 5.2 ) • Estrogen-dependent neoplasia ( 4 , 5.2 ) • Active DVT, PE, or history of these conditions ( 4 , 5.1 ) • Active arterial thromboembolic disease (e.g., stroke and MI), or history of these conditions ( 4 , 5.1 ) • Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel 0.1% ( 4 ) • Hepatic impairment or disease ( 4 , 5.10 ) • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

6 ADVERSE REACTIONS The most common adverse reactions (incidence >5 percent and greater than placebo) in any estradiol gel 0.1% treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Pvt. Ltd. 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The most common adverse reactions (incidence >5 percent and greater than placebo) in any estradiol gel 0.1% treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Pvt. Ltd. 1-833-285-4151 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. Estradiol gel 0.1% was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse reactions that occurred at a rate greater than 5 percent and greater than placebo in any of the treatment groups are summarized in Table 1. Table 1: Number (%) of Subjects with Common Adverse Reactions* in a 12-Week Placebo-Controlled Study of estradiol gel 0.1% Estradiol Gel 0.1% Placebo SYSTEM ORGAN CLASS Preferred Term 0.25 grams/day N=122 n (%) 0.5 grams/day N=123 n (%) 1.0 gram/day N=125 n (%) N=125 n (%) INFECTIONS & INFESTATIONS Nasopharyngitis Upper Respiratory Tract Infection Vaginal mycosis 7 (5.7) 7 (5.7) 1 (0.8) 5 (4.1) 3 (2.4) 3 (2.4) 6 (4.8) 2 (1.6) 8 (6.4) 5 (4.0) 2 (1.6) 4 (3.2) REPRODUCTIVE SYSTEM & BREAST DISORDERS Breast Tenderness Metrorrhagia 3 (2.5) 5 (4.1) 7 (5.7) 7 (5.7) 11 (8.8) 12 (9.6) 2 (1.6) 2 (1.6) *Adverse reactions reported by >5 percent of patients in any treatment group. In a 12-week placebo-controlled study of estradiol gel 0.1%, application site reactions were seen in < 1 percent of participating women. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Estradiol gel 0.1%. 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 Amenorrhea, dysmenorrhea, ovarian cyst, vaginal discharge Breasts Gynecomastia Cardiovascular Palpitations, ventricular extrasystoles Gastrointestinal Flatulence Skin Rash pruritic, urticaria Eyes Retinal vein occlusion Central Nervous System Tremor Miscellaneous Arthralgia, application site rash, asthenia, chest discomfort, fatigue, feeling abnormal, heart rate increased, insomnia, malaise, muscle spasms, pain in extremity, weight increased

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 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 gel 0.1% is not indicated for use in pregnant women. There are no data with the use of estradiol gel 0.1% 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 (estrogen 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 breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for estradiol gel 0.1% and any potential adverse effects on the breastfed child from estradiol gel 0.1% or from the underlying maternal condition. 8.4 Pediatric Use Estradiol gel 0.1% is 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 studies utilizing estradiol gel 0.1% to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel 0.1%. 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 Warnings and Precautions ( 5.1 ) and 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 Warnings and Precautions ( 5.1 , 5.2 ), and 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 ( 14.3 )] . 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 ( 5.3 ), 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, 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 Estradiol gel 0.1percent, is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm2) of the thigh in a thin layer. Estradiol gel 0.1% is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). The active component of the topical gel is estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3, 5(10)-triene-3,17ß-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.39. The structural formula is: The remaining components of the gel alcohol 59.61% v/v, carbopol 974 P polymer, propylene glycol, purified water, and trolamine 99% are pharmacologically inactive. str

10 OVERDOSAGE Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of estradiol gel 0.1% therapy with institution of appropriate symptomatic care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol gel 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, 0.75, 1.0, and 1.25 grams, corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively. NDC 21922-086-52, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet NDC 21922-087-52, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet NDC 21922-088-52, carton of 30 packets, 0.75 mg estradiol per single-dose foil packet NDC 21922-089-52, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet NDC 21922-090-52, carton of 30 packets, 1.25 mg estradiol per single-dose foil packet Keep out of the reach of children. 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]