Estradiol Transdermal

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

Estradiol gel, 0.1% is available in five doses of 0.25, 0.5, 0.75, 1, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1, and 1.25 mg estradiol USP, respectively). Estradiol gel, 0.1% is a clear, colorless gel, which is odorless when dry. Gel: 0.25, 0.5, 0.75, 1, and 1.25 gram-filled single-dose foil packets containing 0.25, 0.5, 0.75, 1, and 1.25 mg estradiol USP, respectively (3)

Estradiol gel is contraindicated in women with any of the following conditions: Abnormal genital bleeding of unknown etiology [see Warning and Precautions (5.2) ] Current 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 (for example, stroke or MI), or a history of these conditions [see Warning and Precautions (5.1) ] Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel Hepatic impairment or disease [see Warnings and Precautions (5.9) ] 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 (4) Hepatic impairment or disease (4 , 5.9) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)

Cardiovascular Disorders: Increased risk of PE, DVT, and stroke with estrogen-alone therapy. Discontinue if an arterial or venous thrombotic or thromboembolic event occurs. (5.1) Estrogens increase the risk of gallbladder disease (5.4) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5 , 5.6 , 5.8 , 5.9) Monitor thyroid function in women on thyroid replacement therapy (5.10 , 5.21)

5.1 Cardiovascular Disorders Estradiol gel is contraindicated in women with active DVT, PE, stroke, or a history of these conditions [see Contraindications (4) ] . Immediately discontinue estradiol gel if a PE, DVT, or stroke, occurs or is suspected. If feasible, discontinue estradiol gel at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. The safety and efficacy of estradiol gel for the prevention of cardiovascular disorders has not been established. The Women’s Health Initiate (WHI) estrogen-alone trial reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), and stroke, in postmenopausal women (50 to 79 years of age, average age 63.4 years) during 7.2 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] relative to placebo. Analyses were also conducted in women aged 50 to 59 years, a group of women more likely to present with onset of moderate to severe VMS compared to women of other age groups in the trial. Only daily oral 0.625 mg CE was studied in the WHI estrogen-alone trial. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events to lower CE doses, other routes of administration, or other estrogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products [see Clinical Studies (14.2) ] . Venous Thromboembolism In women aged 50 to 59 years, the WHI estrogen-alone trial reported a relative risk for PE of 1.53 (95% confidence interval [CI], 0.63, 3.75) for CE compared to placebo, with an absolute risk difference of 4 per 10,000 women-years (WYs; 10 versus 6). The relative risk for DVT was 1.66 (95% CI 0.75, 3.67) for CE compared to placebo, with a risk difference of 5 per 10,000 WYs (13 versus 8). In the overall study population of women aged 50 to 79 years, the WHI estrogen-alone trial reported a relative risk of PE of 1.35 (95% CI 0.89, 2.05) for CE compared to placebo, with a risk difference of 4 per 10,000 WYs (14 versus 10). The relative risk for DVT was 1.48 (95% 1.06, 2.07) for CE compared to placebo, with a risk difference of 7 per 10,000 WYs (23 versus 15) [see Clinical Studies (14.2) ] . Stroke In women aged 50 to 59 years, the WHI estrogen-alone trial reported a relative risk for stroke of 0.99 (95% 0.53, 1.85) for CE compared to placebo, with a risk difference of -1 per 10,000 WYs (16 versus 17). In the overall study population of women aged 50 to 79 years, the WHI estrogen-alone trial reported a relative risk for stroke of 1.35 (95%, 1.07, 1.70) for CE compared to placebo, with a risk difference of 11 per 10,000 WYs (45 versus 34) [see Clinical Studies (14.2) ] .

5.2 Malignant Neoplasms Endometrial Cancer In estradiol gel-treated menopausal women with a uterus with persistent or recurring abnormal genital bleeding of unknown etiology, perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to assess for endometrial cancer. An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen-alone therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There are, however, possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens [see Warnings and Precautions (5.3) ] . Breast Cancer Surveillance measures for breast cancer, such as breast examinations and mammography, are recommended. The use of estrogen-alone therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation. In the WHI estrogen-alone trial, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer. Among women 50 to 59 years old, the relative risk was 0.82 (95% CI, 0.50, 1.34) for CE compared to placebo, with a risk difference of -5 per 10,000 WYs (24 versus 29). In the overall study population of women aged 50 to 79 years (average age 63.4 years), the relative risk was 0.79 (95% CI, 0.61, 1.02), with a risk difference of -7 per 10,000 WYs (28 versus 35) [see Clinical Studies (14.2) ] . However, a large meta-analysis including 24 prospective studies of postmenopausal women comparing current use of estrogen-only products with use duration of 5 to 14 years (average of 9 years) versus never use reported a relative risk for breast cancer of 1.33 (95% CI, 1.28 to 1.38). 1 Ovarian Cancer A large meta-analysis including 17 prospective studies of postmenopausal women compared current use of estrogen-only products versus never use and reported a relative risk for ovarian cancer of 1.37 (95% CI, 1.26 to 1.50). The duration of hormone therapy use that was associated with an increased risk of ovarian cancer is unknown. 2

5.3 Risks Associated with the Co-administration of Estrogen Plus Progestogen Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. If estradiol gel is administered with a progestogen, there are possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens. Refer to prescribing information for progestogens indicated for the prevention of endometrial hyperplasia in non-hysterectomized women receiving estrogens.

5.4 Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5.5 Hypercalcemia Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including estradiol gel, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

5.6 Visual Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue estradiol gel pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including estradiol gel, if examination reveals papilledema or retinal vascular lesions.

5.7 Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. […]

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) ] . The most common adverse reactions (incidence >5 percent and greater than placebo) in any estradiol gel treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 was studied at doses of 0.25, 0.5 and 1 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 Estradiol Gel Placebo SYSTEM ORGAN CLASS Preferred Term 0.25 grams/day N=122 n (%) 0.5 grams/day N=123 n (%) 1 gram/day N=125 n (%) N=125 n (%) INFECTIONS & INFESTATIONS Nasopharyngitis 7 (5.7) 5 (4.1) 6 (4.8) 5 (4.0) Upper Respiratory Tract Infection 7 (5.7) 3 (2.4) 2 (1.6) 2 (1.6) Vaginal mycosis 1 (0.8) 3 (2.4) 8 (6.4) 4 (3.2) REPRODUCTIVE SYSTEM & BREAST DISORDERS Breast Tenderness 3 (2.5) 7 (5.7) 11 (8.8) 2 (1.6) Metrorrhagia 5 (4.1) 7 (5.7) 12 (9.6) 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, 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. 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

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) .

8.1 Pregnancy Risk Summary Estradiol gel is not indicated for use in pregnant women. There are no data with the use of estradiol gel 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 and any potential adverse effects on the breastfed child from estradiol gel or from the underlying maternal condition.

8.4 Pediatric Use Estradiol gel 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 clinical studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. The Women’s Health Initiative Studies In the WHI estrogen-alone trial (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) ] . 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 probable dementia in women receiving estrogen-alone [see Clinical Studies (14.3) ] . Since the trial was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Clinical Studies (14.3) ] . The safety and efficacy of estradiol gel for the prevention of dementia has not been established.

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.