استرادیول

درج واژینال استرادیول یک استروژن است که برای درمان واژینیت آتروفیک ناشی از یائسگی نشان داده شده است (1.1)

1.1 درمان واژینیت آتروفیک ناشی از یائسگی

به طور کلی، هنگامی که استروژن برای یک زن یائسه دارای رحم تجویز می شود، افزودن پروژسترون را برای کاهش خطر سرطان آندومتر در نظر بگیرید. به طور کلی، یک زن بدون رحم نیازی به استفاده از پروژسترون در کنار استروژن درمانی ندارد. با این حال، در برخی موارد، زنان هیسترکتومی شده با سابقه اندومتریوز ممکن است به پروژسترون نیاز داشته باشند [به هشدارها و اقدامات احتیاطی (5.3، 5.15) مراجعه کنید]. از استروژن به تنهایی یا در ترکیب با پروژسترون در کمترین دوز موثر و برای کوتاه ترین مدت مطابق با اهداف و خطرات درمانی برای هر زن استفاده کنید. ارزیابی مجدد زنان یائسه به صورت دوره ای به عنوان مناسب بالینی برای تعیین اینکه آیا درمان هنوز ضروری است یا خیر. تزریقات واژینال استرادیول را به صورت داخل واژینال تجویز کنید: روزانه 1 تزریق به مدت 2 هفته، و به دنبال آن 1 تزریق دو بار در هفته (به عنوان مثال سه شنبه و جمعه) (2.1)

2.1 درمان واژینیت آتروفیک ناشی از یائسگی تزریق واژینال استرادیول را به صورت داخل واژینال با استفاده از اپلیکاتور ارائه شده تجویز کنید: روزانه 1 بار به مدت 2 هفته و سپس 1 بار در هفته دو بار در هفته (به عنوان مثال سه شنبه و جمعه).

درج‌های واژینال استرادیول، USP، سفید تا مایل به سفید، گرد، روکش‌شده، لایه‌بندی نشده و دو محدب حاوی 10 میکروگرم استرادیول هستند. قطر هر درج واژینال 6 میلی متر است و در اپلیکاتور یکبار مصرف تزریق می شود. درج واژینال: یک 10 میکروگرم واژینال حاوی 10.3 میکروگرم استرادیول همی هیدرات معادل 10 میکروگرم استرادیول است (3).

تزریق واژینال استرادیول در زنان با هر یک از شرایط زیر منع مصرف دارد: خونریزی غیر طبیعی دستگاه تناسلی تشخیص داده نشده [به هشدارها و اقدامات احتیاطی (5.3) مراجعه کنید]. سرطان سینه یا سابقه سرطان پستان [به هشدارها و اقدامات احتیاطی (5.3) مراجعه کنید]. نئوپلازی وابسته به استروژن [به هشدارها و اقدامات احتیاطی (5.3) مراجعه کنید]. DVT فعال، PE، یا سابقه این شرایط [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید]. بیماری ترومبوآمبولیک شریانی فعال (به عنوان مثال، سکته مغزی یا MI)، یا سابقه این شرایط [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید]. واکنش آنافیلاکتیک شناخته شده، یا آنژیوادم، یا حساسیت مفرط به استرادیول درج های واژن [به هشدارها و اقدامات احتیاطی (5.16) مراجعه کنید]. نارسایی یا بیماری کبدی. کمبود پروتئین C، پروتئین S یا آنتی ترومبین، یا سایر اختلالات ترومبوفیلیک شناخته شده. خونریزی غیرطبیعی تناسلی تشخیص داده نشده (4، 5.3) سرطان سینه یا سابقه سرطان پستان (4، 5.3) نئوپلازی وابسته به استروژن (4، 5.3) فعال DVT، PE، یا سابقه این شرایط (4، 5.2) سابقه بیماری شریانی فعال استرومبولیکی (مثلاً بیماری های شریانی یا MI) (4، 5.2) واکنش آنافیلاکتیک شناخته شده، آنژیوادم، یا حساسیت مفرط به استرادیول درج های واژینال (4، 5.16) نارسایی یا بیماری کبدی (4، 5.11) پروتئین C، پروتئین S یا کمبود آنتی ترومبین، یا سایر اختلالات ترومبوفیلیک شناخته شده (4)

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 )

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

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.

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 )] .

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.

Estradiol vaginal inserts are not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

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 )] .

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

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.

12.2 Pharmacodynamics Generally, a serum concentration does not predict an individual woman’s therapeutic response to estradiol vaginal inserts nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

12.3 Pharmacokinetics Absorption Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism. In a single-center, randomized, open-label, multiple-dose study conducted in 29 patients, estradiol vaginal inserts 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2). Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Estradiol 10 mcg Uncorrected for baseline, N=29 E2 E1 E1S AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93 53.57 Day 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48 50.07 14 Day 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53 49.76 83 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks. b CV: Coefficient of Variance for both AUC 0-24 and C ave(0-24) Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

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.

Generally, a serum concentration does not predict an individual woman’s therapeutic response to estradiol vaginal inserts nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

Absorption Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism. In a single-center, randomized, open-label, multiple-dose study conducted in 29 patients, estradiol vaginal inserts 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2). Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Estradiol 10 mcg Uncorrected for baseline, N=29 E2 E1 E1S AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93 53.57 Day 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48 50.07 14 Day 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53 49.76 83 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks. b CV: Coefficient of Variance for both AUC 0-24 and C ave(0-24) Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.3 )] . Possible Serious Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )] . Possible Common Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. F 4/2024

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Do not refrigerate.