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| Product NDC Code | 63629-8803 | ||||
|---|---|---|---|---|---|
| Drug Name | Estradiol |
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| Type | Generic | ||||
| Pharm Class | Estradiol Congeners [CS], Estrogen Receptor Agonists [MoA], Estrogen [EPC] |
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| Active Ingredients |
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| Route | VAGINAL | ||||
| Dosage Form | INSERT | ||||
| RxCUI drug identifier | 884707 | ||||
| Application Number | ANDA206388 | ||||
| Labeler Name | Bryant Ranch Prepack | ||||
| Packages |
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| Check if available Online | Get Medication Prices online with Discount |
Overdosage of Estradiol
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.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.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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 )] In a prospective, randomized, placebo-controlled, double-blind study the most common adverse reactions (incidence ≥5 percent) were back pain, vulvovaginal pruritus, vulvovaginal mycotic infection and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. 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 Repro ductive 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 Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.
Estradiol Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted for estradiol. Inducers and 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 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 side effects.
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 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 Currently, there are no pharmacodynamic data known for estradiol. 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 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 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. of Estradiol 10 mcg Uncorrected for baseline, N = 29 E2 E1 E1S AUC 0-24 C ave (0-24) %CV CV: Coefficient of Variance for both AUC 0-24 and C ave(0-24) AUC 0-24 C ave (0-24) %CV AUC 0-24 C ave (0-24) %CV (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 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. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.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.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for estradiol.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.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 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 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. of Estradiol 10 mcg Uncorrected for baseline, N = 29 E2 E1 E1S AUC 0-24 C ave (0-24) %CV CV: Coefficient of Variance for both AUC 0-24 and C ave(0-24) AUC 0-24 C ave (0-24) %CV AUC 0-24 C ave (0-24) %CV (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 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. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Estradiol vaginal inserts should not be used 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 myocardial infarction), or a history of these conditions Known anaphylactic reaction or angioedema to estradiol vaginal inserts 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 , 5.3 ) Known or suspected estrogen-dependent neoplasia ( 4 , 5.3 ) Active DVT, PE, or history of these conditions ( 4 , 5.2 ) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.2 ) Known anaphylactic reaction or angioedema to estradiol vaginal inserts Known liver impairment or disease ( 4 , 5.11 ) Known protein C, protein S, or antithrombin deficient, or other known thrombophilic disorders ( 4 ) Known or suspected pregnancy ( 4 , 8.1 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.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) USP Dissolution Test pending.
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.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 ( 5.3 , 5.15 )] . 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. Estradiol vaginal inserts should be administered 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 Estradiol vaginal inserts should be administered intravaginally using the supplied applicator: 1 insert daily for 2 weeks, followed by 1 insert twice weekly (for example, Tuesday and Friday).
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.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. Estradiol vaginal inserts: One vaginal insert contains 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Estradiol vaginal inserts are an estrogen (estradiol) indicated for the treatment of atrophic vaginitis due to menopause ( 1.1 ) 1.1 Treatment of Atrophic Vaginitis due to Menopause
Spl product data elements
Usually a list of ingredients in a drug product.Estradiol Estradiol ESTRADIOL ESTRADIOL STARCH, CORN HYPROMELLOSE 2208 (100 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 6000 white to off-white TV;T5 Chemical structure Figure A Figure B Figure C Figure D Figure A Figure B Figure C Figure D
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, 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.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.Estradiol Vaginal Inserts 10 mcg #8 Label
Estradiol: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. 17.1 Vaginal Bleeding Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.3 )] . 17.2 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 )] . 17.3 Possible Less Serious but 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. 17.4 Instructions for Use of Applicator Step 1: Tear off a single applicator. Step 2: Separate the plastic wrap and remove the applicator from the plastic wrap as shown in Figure A. If after opening the package you see that the insert has come out of the applicator but has not fallen out of the package, carefully put it back into the applicator for insertion. Please keep your hands clean and dry while handling the insert . Step 3: Hold the applicator so that the finger of one hand can press the applicator plunger as shown in Figure B. Step 4: Next select the best position for vaginal insertion of estradiol vaginal inserts that is most comfortable for you. See suggested reclining Figure C or standing Figure D position illustrated below: Step 5: Using the other hand, guide the applicator gently and comfortably through the vaginal opening (see Figures C and D above). If prior to insertion the insert falls out of the applicator, throw the insert and applicator away and use a new insert-filled applicator . Step 6: The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less. Step 7: Once the insert-filled applicator has been inserted, gently press the plunger until the plunger is fully depressed. This will eject the insert inside your vagina where it will dissolve slowly over several hours. Step 8: After depressing the plunger, gently remove the applicator and dispose of it the same way you would a plastic tampon applicator. The applicator is of no further use and should be discarded properly. Insertion may be done at any time of the day. It is advisable to use the same time daily for all applications of estradiol vaginal inserts. If you have any questions, please consult your healthcare provider or pharmacist. Teva Women's Health, Inc. Subsidiary of Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Rev. D 5/2019
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.FDA-Approved Patient Labeling Estradiol (ess tra DYE ole) Vaginal Inserts Read this PATIENT INFORMATION before you start using estradiol vaginal inserts and read what you get each time you refill your estradiol vaginal inserts prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment. What is the most important information I should know about estradiol vaginal inserts (an estrogen hormone) Using estrogen-alone may increase your chance of getting cancer of the uterus (womb) Report any unusual vaginal bleeding right away while you are using estradiol vaginal inserts. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline of brain function) Using estrogen-alone may increase your chances of getting strokes or blood clots Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older Do not use estrogens with progestins to prevent heart disease, heart attack, strokes or dementia Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots Using estrogens with progestin may increase your chance of getting dementia, based on a study of women 65 years of age or older You and your healthcare provider should talk regularly about whether you still need treatment with estradiol vaginal inserts What are estradiol vaginal inserts? Estradiol vaginal inserts are a medicine that contains estradiol (an estrogen hormone) in a vaginal insert. What are estradiol vaginal inserts used for? Estradiol vaginal inserts are used after menopause to: Treat menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with estradiol vaginal inserts to control these problems. Who should not use estradiol vaginal inserts? Do not start using estradiol vaginal inserts if you: Have unusual vaginal bleeding Currently have or have had certain cancers Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol vaginal inserts. Had a stroke or heart attack Currently have or have had blood clots Currently have or have had liver problems Have been diagnosed with a bleeding disorder Are allergic to estradiol vaginal inserts or any of its ingredients See the list of ingredients in estradiol vaginal inserts at the end of this leaflet. Think you may be pregnant Tell your healthcare provider: If you have any unusual vaginal bleeding Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. About all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. About all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol vaginal inserts work. Estradiol vaginal inserts may also affect how your other medicines work. If you are going to have surgery or will be on bed rest You may need to stop using estradiol vaginal inserts. If you are breast feeding The hormone in estradiol vaginal inserts can pass into your breast milk. How should I use estradiol vaginal inserts? Estradiol vaginal inserts are an insert that you place in your vagina with an applicator. Take the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for you Estrogens should be used at the lowest dose possible for your treatment only as long as needed You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are using and whether you still need treatment with estradiol vaginal inserts. Step 1: Tear off a single applicator. Step 2: Separate the plastic wrap and remove the applicator from the plastic wrap as shown in Figure A. If after opening the package you see that the insert has come out of the applicator but has not fallen out of the package, carefully put it back into the applicator for insertion. Please keep your hands clean and dry while handling the insert. Step 3: Hold the applicator so that the finger of one hand can press the applicator plunger as shown in Figure B. Step 4: Next select the best position for vaginal insertion of estradiol vaginal inserts that is most comfortable for you. See suggested reclining Figure C or standing Figure D position illustrated below: Step 5: Using the other hand, guide the applicator gently and comfortably through the vaginal opening (see Figures C and D above). If prior to insertion the insert falls out of the applicator, throw the insert and applicator away and use a new insert-filled applicator. Step 6: The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less. Step 7: Once the insert-filled applicator has been inserted, gently press the plunger until the plunger is fully depressed. This will eject the insert inside your vagina where it will dissolve slowly over several hours. Step 8: After depressing the plunger, gently remove the applicator and dispose of it the same way you would a plastic tampon applicator. The applicator is of no further use and should be discarded properly. Insertion may be done at any time of the day. It is advisable to use the same time daily for all applications of estradiol vaginal inserts. If you have any questions, please consult your healthcare provider or pharmacist. Dosage Estradiol vaginal insert therapy consists of the following dosing regimen: One (1) estradiol vaginal insert intravaginally once daily for the first two (2) weeks, then one (1) insert twice weekly (for example Tuesday and Friday) for as long as you use estradiol vaginal inserts. What are the possible side effects of estradiol vaginal inserts? Estradiol vaginal inserts are only used in the vagina; however, the risks associated with oral estrogens should be taken into account. Side effects are grouped by how serious they are and how often they happen when you are treated. Serious but less common side effects include: Heart attack Stroke Blood clots Dementia Breast cancer Cancer of the lining of the uterus (womb) Cancer of the ovary High blood pressure High blood sugar Gallbladder disease Liver problems Enlargement of benign tumors of the uterus (“fibroids”) Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: New breast lumps Unusual vaginal bleeding Changes in vision or speech Sudden new severe headaches Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue Less serious, but common, side effects include: Headache Breast pain Irregular vaginal bleeding or spotting Stomach or abdominal cramps, bloating Nausea and vomiting Hair loss Fluid retention Vaginal yeast infection These are not all the possible side effects of estradiol vaginal inserts. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with estradiol vaginal inserts? Talk with your healthcare provider regularly about whether you should continue using estradiol vaginal inserts. If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while using estradiol vaginal inserts. Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. General information about the safe and effective use of estradiol vaginal inserts. Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use estradiol vaginal inserts for conditions for which they were not prescribed. Do not give estradiol vaginal inserts to other people, even if they have the same symptoms you have. They may harm them. Keep estradiol vaginal inserts out of the reach of children. This leaflet provides a summary of the most important information about estradiol vaginal inserts. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol vaginal inserts that is written for health professionals. You can get more information by calling the toll free number 1-888-838-2872. What are the ingredients in estradiol vaginal inserts? Estradiol vaginal inserts are small, white, round, film-coated, unscored, biconvex inserts containing estradiol. Each insert also contains corn starch, hypromellose, lactose monohydrate, magnesium stearate, and polyethylene glycol. Each estradiol vaginal insert is contained in a disposable applicator, packaged in a blister pack. Cartons contain 8 or 18 applicators with inset inserts. Store at 68° to 77°F (20° to 25°C). Do not refrigerate. Teva Women's Health, Inc. Subsidiary of Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Rev. C 5/2019
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Effects on Atrophic Vaginitis A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of estradiol 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean 57.6 years of age) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse). Women inserted one insert intravaginally each day for 14 days, then one insert twice weekly for the remaining 50 weeks. The majority (92.9 percent) of the women were Caucasian (n = 287), 3.2 percent were Black (n = 10), 1.6 percent were Asian (n = 5) and 2.2 percent were Other (n = 7). All subjects were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH. Relief of Vaginal Symptoms Estradiol 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 3). Table 3: Mean Change from Baseline to Week 12 in a Composite Score of Most Bothersome Symptoms Compared to Placebo – ITT Population All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation. Placebo Estradiol 10 mcg ITT Population N 93 190 Baseline mean composite score 2.29 2.35 Change from baseline at Week 12 (LOCF) -0.84 -1.20 p-value versus Placebo --- 0.002 Also demonstrated for estradiol 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p < 0.001), a statistically significant decrease in parabasal cells at Week 12 (-37.0 percent compared to -9.3 percent for matching placebo, p < 0.001), and a statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p < 0.001). Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 subjects in the estradiol 10 mcg group who had a biopsy performed at end of study, 92 subjects had endometrial tissue that was atrophic or inactive and 73 subjects had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia. Three subjects exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation. Endometrial safety of estradiol 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 subjects who had a biopsy performed at end of study, 183 subjects had endometrial tissue that was atrophic or inactive and 111 subjects had no tissue or tissue insufficient for diagnosis. There was one case of complex hyperplasia without atypia. Two subjects exhibited polyps. 14.2 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 4. Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Event Relative Risk CE Placebo CE vs. Placebo n = 5,310 n = 5,429 (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) Absolute Risk per 10,000 Women-Years CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78 to 1.16) 54 57 Non-fatal MI 0.91 (0.73 to 1.14) 40 43 CHD death 1.01 (0.71 to 1.43) 16 16 All Strokes 1.33 (1.05 to 1.68) 45 33 Ischemic stroke 1.55 (1.19 to 2.01) 38 25 Deep vein thrombosis , Not included in “global index”. 1.47 (1.06 to 2.06) 23 15 Pulmonary embolism 1.37 (0.90 to 2.07) 14 10 Invasive breast cancer 0.80 (0.62 to 1.04) 28 34 Colorectal cancer Results are based on an average follow-up of 6.8 years. 1.08 (0.75 to 1.55) 17 16 Hip fracture 0.65 (0.45 to 0.94) 12 19 Vertebral fractures , 0.64 (0.44 to 0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47 to 0.72) 35 59 Total fractures , 0.71 (0.64 to 0.80) 144 197 Death due to other causes , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88 to 1.32) 53 50 Overall mortality , 1.04 (0.88 to 1.22) 79 75 Global Index A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92 to 1.13) 206 201 For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years. Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined. 10 Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)] . WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. , Results are based on centrally adjudicated data. Event Relative Risk CE/MPA Placebo CE/MPA vs Placebo n = 8,506 n = 8,102 (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99 to 1.53) 41 34 Non-fatal MI 1.28 (1.00 to 1.63) 31 25 CHD death 1.10 (0.70 to 1.75) 8 8 All Strokes 1.31 (1.03 to 1.68) 33 25 Ischemic stroke 1.44 (1.09 to 1.90) 26 18 Deep vein thrombosis Not included in “global index”. 1.95 (1.43 to 2.67) 26 13 Pulmonary embolism 2.13 (1.45 to 3.11) 18 8 Invasive breast cancer Includes metastatic and non-metastatic breast cancer, with the exception of in situ cancer. 1.24 (1.01 to 1.54) 41 33 Colorectal cancer 0.61 (0.42 to 0.87) 10 16 Endometrial cancer 0.81 (0.48 to 1.36) 6 7 Cervical cancer 1.44 (0.47 to 4.42) 2 1 Hip fracture 0.67 (0.47 to 0.96) 11 16 Vertebral fractures 0.65 (0.46 to 0.92) 11 17 Lower arm/wrist fractures 0.71 (0.59 to 0.85) 44 62 Total fractures 0.76 (0.69 to 0.83) 152 199 Overall Mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83 to 1.19) 52 52 Global Index A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.13 (1.02 to 1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44 to 1.07)] . 14.3 Women’s Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominately healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.4 ), and Use in Specific Populations ( 8.5 )] . The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.4 ), and Use in Specific Populations ( 8.5 )] . When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.4 ), and Use in Specific Populations ( 8.5 )] .
References
This field may contain references when prescription drug labeling must summarize or otherwise relay on a recommendation by an authoritative scientific body, or on a standardized methodology, scale, or technique, because the information is important to prescribing decisions.15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007; 297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006; 166:357-365. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006; 166:772-780. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004; 292:1573-1580. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA . 2006; 295:1647-1657. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA . 2003; 289:3234-3253. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic cancers and Associated Diagnostic Procedures. JAMA . 2003; 290:1739-1748. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA . 2004; 291:2947-2958. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women’s Health Initiative Randomized Trial. J Bone Miner Res . 2006; 21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative. Circulation . 2006; 113:2425-2434.
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing estradiol to determine whether those over 65 years of age differ from younger subjects in their response to estradiol. 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 )] .
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.3 Nursing Mothers Estradiol 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 therapy. Caution should be exercised when estradiol is administered to a nursing woman.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Estradiol is not indicated in children. Clinical studies have not been conducted in the pediatric population.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Estradiol 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk ( 8.3 ) Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women’s Health Initiative Memory ancillary studies of the Women’s Health Initiative ( 8.5 ) 8.1 Pregnancy Estradiol 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 Estradiol 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 therapy. Caution should be exercised when estradiol is administered to a nursing woman. 8.4 Pediatric Use Estradiol is not indicated in children. 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 to determine whether those over 65 years of age differ from younger subjects in their response to estradiol. 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 )] . 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of estradiol has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of estradiol has not been studied.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.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 applicators with inset inserts. Estradiol vaginal inserts USP, 10 mcg: 8 applicators: NDC: 63629-8803-1 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.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.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 ( 5.3 )] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.2 , 5.4 ), and Clinical Studies ( 14.2 , 14.3 )] . 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 ( 5.2 ), and Clinical Studies ( 14.2 )] . The WHI Memory Study (WHIMS) estrogen-alone ancillary study of 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 ( 5.4 ), Use in Specific Populations ( 8.5 ), 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 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 ( 5.2 , 5.4 ), and Clinical Studies ( 14.2 , 14.3 )] . 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 ( 5.2 ), and Clinical Studies ( 14.2 )] . The WHIMS estrogen plus progestin ancillary study of the WHI reported an 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 ( 5.4 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.3 )] . 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 ( 14.2 )] . 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 ( 5.3 ) Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.2 , 5.4 ) The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.2 ) 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 ( 5.4 ) Estrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.2 , 5.4 ) The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI) ( 5.2 ) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.3 ) 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 ( 5.4 )
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API