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| Product NDC Code | 0574-2067 | ||||||
|---|---|---|---|---|---|---|---|
| Drug Name | Evamist |
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| Type | Brand | ||||||
| Pharm Class | Estradiol Congeners [CS], Estrogen Receptor Agonists [MoA], Estrogen [EPC] |
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| Active Ingredients |
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| Route | TRANSDERMAL | ||||||
| Dosage Form | SPRAY | ||||||
| RxCUI drug identifier | 728118, 728122 |
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| Application Number | NDA022014 | ||||||
| Labeler Name | Padagis US LLC | ||||||
| Packages |
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Overdosage of Evamist
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 and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Evamist 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 ( 5.1 )] • Malignant Neoplasms [see Boxed Warning, Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥ 5 percent) with Evamist are: headache, breast tenderness and nipple pain, nausea, back pain, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 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 clinical practice. In a 12-week, randomized, placebo-controlled trial of Evamist in 454 women, 80 to 90 percent of women randomized to active drug received at least 70 days of therapy and 75 to 85 percent randomized to placebo received at least 70 days of therapy. The adverse reactions that occurred in at least 5 percent of women in any treatment group are shown in Table 1. Table 1. Frequency of Adverse Reactions (≥5%) in Any Treatment Group in a Controlled Study of Evamist Frequency n (%) System Organ Class Preferred Term 1 Spray 2 Sprays 3 Sprays Placebo (N = 77) Evamist (N = 76) Placebo (N = 76) Evamist (N = 74) Placebo (N = 75) Evamist (N = 76) Reproductive System and Breast Disorders Breast tenderness 0 (0) 4 (5) 4 (5) 5 (7) 0 (0) 4 (5) Nipple pain 0 (0) 2 (3) 0 (0) 5 (7) 0 (0) 1 (1) Gastrointestinal Disorders Nausea 5 (7) 1 (1) 1 (1) 2 (3) 4 (5) 2 (3) Infections and Infestations Nasopharyngitis 1 (1) 4 (5) 2 (3) 3 (4) 1 (1) 1 (1) Musculoskeletal and Connective Tissue Disorders Back pain 1 (1) 2 (3) 2 (3) 4 (5) 1 (1) 2 (3) Arthralgia 1 (1) 1 (1) 4 (5) 1 (1) 0 (0) 3 (4) Nervous system Headache 4 (5) 7 (9) 5 (7) 9 (12) 7 (9) 8 (11) Application site reactions were reported in 3 out of 226 (1.3%) women treated with Evamist. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Evamist. 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. Breasts: Breast swelling, breast mass, breast enlargement Cardiovascular: Heart rate increased Central nervous system: Dizziness, dysgeusia, paresthesia, lethargy, hypoesthesia Eyes: Eye irritation, ocular hyperemia Gastrointestinal: Abdominal pain, diarrhea, constipation, abdominal distension, dry mouth, decreased appetite Genitourinary system: Vaginal bleeding Musculoskeletal: Muscle spasms, arthritis Psychiatric: Insomnia, mood swings, anxiety, irritability, mood altered, depression Respiratory tract: Cough, dyspnea, dry throat Skin: Nipple and areola discoloration, usually on the same side of the body as the inner forearm on which Evamist is applied, rash, pruritus, alopecia, urticaria, dry skin, skin discoloration, chloasma Miscellaneous: Weight increased, malaise, fatigue, asthenia
Evamist 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 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. ( 7.1 )
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 Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to Evamist 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 In a multiple-dose study, 72 postmenopausal women were treated for 14 days with Evamist to the inner forearm. Serum concentrations of estradiol appeared to reach steady state after 7 to 8 days of application of one, two, or three 90 mcL sprays of Evamist per day (Figure 1). Figure 1. Mean (±SD) Serum Estradiol Concentrations on Day 14 Following Topical Application for 14 Days of One, Two or Three Sprays of Evamist (Unadjusted for Baseline) Pharmacokinetics parameters for estradiol from one, two, or three 90 mcL sprays of Evamist, as assessed on Day 14 of this study, are described in Table 2. Table 2. Estradiol Pharmacokinetic Parameters on Day 14 (Unadjusted for Baseline) PK Parameter Number of Daily Sprays of Evamist 1 Spray (N = 24) 2 Sprays (N = 23) 3 Sprays (N = 24) C max (pg/mL) a C min (pg/mL) a C avg (pg/mL) a AUC 0-24 (pg*hr/mL) a T max (hours) b 36.4 (62) 11.3 (52) 19.6 (49) 471 (49) 20 (0-24) 57.4 (94) 18.1 (51) 30.7 (43) 736 (43) 18 (0-24) 54.1 (50) 19.6 (27) 30.9 (30) 742 (30) 20 (0-24) a Values expressed are arithmetic means (%CV) b Values expressed are medians (minimum-maximum) 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 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 a 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 intestine followed by reabsorption. In postmenopausal women, a significant proportion 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. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in 20 healthy postmenopausal women who applied three 90-mcL sprays of Evamist to the inner forearm once daily. One hour after applying Evamist, subjects held the dosed forearm against the inner forearm of a non-dosed (recipient) male subject for one 5-minute period of continual contact. A 4% increase in serum estradiol exposure was observed in persons who came in contact with the application site. The possibility of unintentional secondary exposure to Evamist should be brought to the attention of physicians and Evamist users. Effect of Application Site Washing Site washing with warm water and soap one hour after the application of three 90 mcL sprays to the inner forearm did not have a significant effect on average 24-hour serum concentrations of estradiol. Figure 1
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 Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to Evamist 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.
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 In a multiple-dose study, 72 postmenopausal women were treated for 14 days with Evamist to the inner forearm. Serum concentrations of estradiol appeared to reach steady state after 7 to 8 days of application of one, two, or three 90 mcL sprays of Evamist per day (Figure 1). Figure 1. Mean (±SD) Serum Estradiol Concentrations on Day 14 Following Topical Application for 14 Days of One, Two or Three Sprays of Evamist (Unadjusted for Baseline) Pharmacokinetics parameters for estradiol from one, two, or three 90 mcL sprays of Evamist, as assessed on Day 14 of this study, are described in Table 2. Table 2. Estradiol Pharmacokinetic Parameters on Day 14 (Unadjusted for Baseline) PK Parameter Number of Daily Sprays of Evamist 1 Spray (N = 24) 2 Sprays (N = 23) 3 Sprays (N = 24) C max (pg/mL) a C min (pg/mL) a C avg (pg/mL) a AUC 0-24 (pg*hr/mL) a T max (hours) b 36.4 (62) 11.3 (52) 19.6 (49) 471 (49) 20 (0-24) 57.4 (94) 18.1 (51) 30.7 (43) 736 (43) 18 (0-24) 54.1 (50) 19.6 (27) 30.9 (30) 742 (30) 20 (0-24) a Values expressed are arithmetic means (%CV) b Values expressed are medians (minimum-maximum) 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 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 a 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 intestine followed by reabsorption. In postmenopausal women, a significant proportion 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. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in 20 healthy postmenopausal women who applied three 90-mcL sprays of Evamist to the inner forearm once daily. One hour after applying Evamist, subjects held the dosed forearm against the inner forearm of a non-dosed (recipient) male subject for one 5-minute period of continual contact. A 4% increase in serum estradiol exposure was observed in persons who came in contact with the application site. The possibility of unintentional secondary exposure to Evamist should be brought to the attention of physicians and Evamist users. Effect of Application Site Washing Site washing with warm water and soap one hour after the application of three 90 mcL sprays to the inner forearm did not have a significant effect on average 24-hour serum concentrations of estradiol. Figure 1
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 Evamist is contraindicated in women with any of the following conditions: • Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )]. • Breast cancer or a history of breast cancer [see Warnings and Precautions ( 5.2 )]. • Estrogen-dependent neoplasia [see Warnings and Precautions ( 5.2 )]. • Active DVT, PE, or history of these conditions [see Warnings and Precautions ( 5.1 )]. • Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warnings and Precautions ( 5.1 )]. • Known anaphylactic reaction, angioedema, or hypersensitivity to Evamist. • Hepatic impairment or disease. • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. • Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) • 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 (for example, stroke and MI), or history of these conditions ( 4 , 5.1 ) • Known anaphylactic reaction, angioedema, or hypersensitivity to Evamist ( 4 ) • Hepatic impairment or disease ( 4 , 5.10 ) • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )
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 Evamist (estradiol transdermal spray) is designed to deliver estradiol to the blood circulation following topical application to the skin of a rapidly drying solution from a metered-dose pump. Evamist is a homogeneous solution of 1.7% estradiol USP (active ingredient) in alcohol USP and octisalate USP formulated to provide sustained release of the active ingredient into the systemic circulation. Estradiol USP is a white crystalline powder, chemically described as estra-1,3,5(10)-triene- 3,17β-diol. It has an empirical formula of C 18 H 24 O 2 •1/2 H 2 O and molecular weight of 281.4. The structural formula is: Each metered-dose pump contains 8.1 mL and is designed to deliver 56 sprays of 90 mcL each after priming. One spray of Evamist contains 1.53 mg estradiol. The metered-dose pump should be held upright and vertical for spraying. Before a new applicator is used for the first time, the pump should be primed by spraying 5 times with the cover on. One, two or three sprays are applied daily each morning to adjacent non-overlapping 20 cm 2 areas on the inner surface of the arm between the elbow and the wrist and allowed to dry. Structural Formula
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, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.15 )] . Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. • Start therapy with one spray of Evamist once daily each morning to forearm ( 2.1 ) • Dosage adjustment to two or three sprays of Evamist should be guided by the clinical response ( 2.1 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start Evamist therapy with one spray of Evamist per day. Make dosage adjustment based on the clinical response. Prime the Evamist container by spraying 5 sprays with the cover on before applying the first dose from a new applicator. Hold the container upright and vertical for spraying. Apply one, two or three sprays each morning to adjacent, non-overlapping areas on the inner surface of the forearm, starting near the elbow. Allow the sprays to dry for approximately 2 minutes before covering the site with clothing. Do not wash the application site for at least one hour. Application of Evamist to other skin surfaces has not been adequately studied. Evamist should not be applied to skin surfaces other than the forearm. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to estradiol from Evamist-treated skin. Cover the Evamist application site with clothing if another person may come into contact with that area of skin after the spray dries. Additional precautions to minimize unintentional secondary exposure are outlined in Patient Counseling Information [see Patient Counseling Information] and in the Patient Information Leaflet at the end of the prescribing information.
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 Evamist is an estradiol transdermal spray. One spray consists of 90 mcL that contains 1.53 mg of estradiol. • Spray: One spray consists of 90 mcL which contains 1.53 mg 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 Evamist 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.
Spl product data elements
Usually a list of ingredients in a drug product.Evamist Estradiol ESTRADIOL ESTRADIOL OCTISALATE ALCOHOL
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.PACKAGE/LABEL PRINCIPAL DISPLAY PANEL FOR TOPICAL USE ONLY NDC 0574-2067-27 Evamist ® (estradiol transdermal spray) Each spray contains 1.53 mg of estradiol 0.27 fl oz (8.1 mL) Rx Only carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Boxed Warning 08/2023 Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 12/2023
Evamist: 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 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 ( 5.2 )] . Unintentional Secondary Exposure to Evamist Provide the following information about secondary exposure to Evamist: • Apply Evamist as directed and keep children from contacting exposed application site(s). If direct contact with the application site occurs, the contact area should be washed thoroughly with soap and water. Women should cover the Evamist application site, after the 2 minute drying period, with clothing if another person may come in contact with that area of skin. [See FDA-Approved Patient Information Leaflet at the end of the prescribing information.] • Look for signs of unexpected sexual development, such as breast mass or increased breast size in prepubertal children. • If signs of unintentional secondary exposure are noticed: o Have children evaluated by a healthcare provider. o Discontinue Evamist until the cause(s) is identified for any unexpected sexual development in children under their care. o Women should contact their healthcare provider and discuss the appropriate use and handling of Evamist when around children. o If conditions for safe use cannot be met, Evamist should be discontinued and alternative treatments for menopausal signs and symptoms should be considered. • Pets may also be unintentionally exposed to Evamist if above precautions are not followed. Possible Serious Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of the possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . 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 by Padagis ® Yeruham, Israel www.padagis.com Rev 10-2024 9E400 RC PH3
Instructions for use
Information about safe handling and use of the drug product.Instructions for Use EVAMIST (EE-vuh-mist) (estradiol transdermal spray) Read this Instructions for Use before you start using EVAMIST and each time you get a refill. 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. The parts of your EVAMIST applicator EVAMIST comes in a spray applicator that delivers a measured amount of estradiol to your skin with each spray (see Figure A). Step 1. Priming your EVAMIST • Before you use your EVAMIST applicator for the first time, the applicator must be primed. • Hold the EVAMIST applicator upright. Keep the cover on. Fully press down the pump button 5 times with your thumb or index finger (see Figure B). After priming, the EVAMIST applicator is ready to use. • The EVAMIST applicator should be primed only 1 time when you first start using a new applicator. Do not prime the EVAMIST applicator before your dose each day. Step 2. Using your EVAMIST • Remove the plastic cover. • Apply EVAMIST to a clean, dry, unbroken skin area on the inside of your forearm between the elbow and the wrist (see Figure C). This area must be clean, dry, and the skin must be without open wounds, cuts, abrasions, or rashes. • Hold the EVAMIST applicator upright and rest the plastic cone flat against your skin. You may need to change the position of your arm or the position of the cone on your arm so that the cone is flat against your skin and there are no gaps between the cone and your skin (see Figure C). • Press the pump button down fully 1 time (see Figure C). If your healthcare provider tells you to increase your dose to 2 or 3 sprays, move the cone before applying the second or third spray to an area of your skin next to but not touching the area of the previous spray (see Figure D). • Do not apply EVAMIST to your breasts or in and around your vagina. • Do not massage or rub EVAMIST into your skin. • Let EVAMIST spray dry on your skin for at least: o 2 minutes before you cover your skin with clothing. o 1 hour before you wash your skin. Step 3. After you use EVAMIST • Place the plastic cover back on the EVAMIST applicator cone. • EVAMIST is flammable until dry. Avoid fire, flame, or smoking until the area of your skin where you have applied EVAMIST has completely dried. Step 4. Throwing away used EVAMIST applicators • Your EVAMIST applicator contains enough medicine to allow for initial priming of the pump with 5 sprays and application of 56 sprays. • Do not use your EVAMIST applicator for more than 56 application sprays even though the bottle may not be completely empty. You may not get the correct dose. • Always replace the cover over the cone of your EVAMIST applicator before you throw it away to prevent accidental exposure to other people or pets. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured by Padagis ® Yeruham, Israel www.padagis.com Rev 10-2024 9E400 RC PH3 Figure A Figure B Figure C Figure D
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.Patient Information EVAMIST (EE-vuh-mist) (estradiol transdermal spray) Read this Patient Information before you start using EVAMIST and each time you get a refill. 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 EVAMIST (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 EVAMIST. 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 in 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 and older. • Do not use estrogens with progestogens to prevent heart disease, heart attack, strokes, or dementia. • Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. • Using estrogens with progestogens may increase your chance of getting dementia, based on a study of women 65 years and older. • The estrogen in EVAMIST spray can transfer from the area of skin where it was sprayed to other people. Do not allow others, especially children, to come into contact with the area of your skin where you sprayed EVAMIST. Young children who are accidentally exposed to estrogen through contact with women using EVAMIST may show signs of puberty that are not expected (for example, breast budding). • Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of EVAMIST will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with EVAMIST. What is EVAMIST? EVAMIST is a prescription medicine spray that contains estradiol (an estrogen hormone). What is EVAMIST used for? EVAMIST spray is used after menopause to: • Reduce moderate to severe hot flashes Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with EVAMIST. Who should not use EVAMIST? Do not start using EVAMIST if you: • have 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. • have been diagnosed with a bleeding disorder. • currently have or have had certain cancers. Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use EVAMIST. • had a stroke or heart attack. • currently have or have had blood clots. • currently have or have had liver problems. • are allergic to EVAMIST or any of its ingredients. See the list of ingredients in EVAMIST at the end of this leaflet Before you use EVAMIST, tell your healthcare provider about all of your medical conditions, including 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 vaginal bleeding to find out the cause. • have any other medical conditions that may become worse while you are using EVAMIST. 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, angioedema (swelling of face or tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop using EVAMIST. • are pregnant or think you may be pregnant. EVAMIST is not for pregnant women. • are breastfeeding. The hormone in EVAMIST can pass into your breast milk. Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements. Some medicines may affect how EVAMIST works. Some other medicines and food products may increase or decrease the concentration of the hormone in EVAMIST in the blood. EVAMIST may affect how your other medicines work, and other medicines may affect how EVAMIST works. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I use EVAMIST? For detailed instructions, see the step-by-step instructions for using EVAMIST at the end of this Patient Information. • Use EVAMIST exactly as your healthcare provider tells you to use it. • EVAMIST is for skin use only. • Apply EVAMIST at the same time each day. • If you use sunscreen 1 hour after you use EVAMIST, it may reduce the amount of EVAMIST absorbed by your skin. • The estrogen in EVAMIST spray can transfer from the area of skin where it was sprayed to other people or pets. Do not allow other people, especially children to come into contact with the area of your skin where you have sprayed EVAMIST. • If another person accidentally touches the area of your skin where you have sprayed EVAMIST, that area of their skin should be washed with soap and water right away. • Do not let pets lick or touch your arm where you have sprayed EVAMIST, especially small pets. EVAMIST may harm them. Cover your skin with clothing where you have sprayed EVAMIST if you think a pet could come in contact with that area of your skin. • If a pet accidentally comes in contact with the area of your skin where you have sprayed EVAMIST, the area of the pet’s skin should be washed with soap and water right away. • Young children who are accidentally exposed to estrogen through contact with women using EVAMIST may show signs and symptoms of puberty that are not expected. Signs and symptoms in children of exposure to EVAMIST may include: o breast budding or breast lumps o other signs of abnormal sexual development If a child shows signs and symptoms of accidental exposure to EVAMIST: o have the child checked right away by their healthcare provider. o stop using EVAMIST and call your healthcare provider right away. o talk to your healthcare provider about the correct use of EVAMIST when around children. • Talk to your healthcare provider about other treatments for your menopause symptoms if accidental exposure to EVAMIST cannot be avoided. • You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with EVAMIST. What should I avoid while using EVAMIST? • Do not allow others to make contact with the area of skin where you have applied the EVAMIST spray. • EVAMIST contains alcohol, which is flammable. Avoid fire, flame, or smoking until the area of your skin where you have applied EVAMIST has dried. What are the possible side effects of EVAMIST? 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 • breast cancer • cancer of the lining of the uterus (womb) • cancer of the ovary • dementia • gallbladder disease • high or low calcium levels • changes in vision • high blood pressure • high levels of fat in your blood (triglycerides) • liver problems • changes in thyroid hormone levels • swelling or fluid retention • cancer changes of endometriosis • enlargement of benign tumors of the uterus (“fibroids”) • worsening swelling of face or tongue (angioedema) in women who have a history of angioedema • changes in laboratory test results such as bleeding time and high blood sugar levels 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 Common side effects of EVAMIST include: • headache • breast pain • irregular vaginal bleeding or spotting • stomach or abdominal cramps, bloating • nausea and vomiting • hair loss • fluid retention • vaginal yeast infection Tell your healthcare provider if you have any side effects that bother you or do not go away. These are not all the possible side effects of EVAMIST. Call your doctor for medical advice about side effects. You may also report side effects to Padagis ® at 1-866-634-9120 or to FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with EVAMIST? • Talk with your healthcare provider regularly about whether you should continue using EVAMIST. • If you have a uterus, talk with your healthcare provider about whether the addition of a progestogen is right for you. • In general, the addition of a progestogen is recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb). • See your healthcare provider right away if you get vaginal bleeding while using EVAMIST. • 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 a higher chance of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store EVAMIST? • Store EVAMIST at room temperature 68°F to 77°F (20°C to 25°C) • Do not freeze. • Safely throw away medicine that is out of date or no longer needed. Keep EVAMIST and all medicines out of the reach of children. General information about the safe and effective use of EVAMIST. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use EVAMIST for a condition for which it was not prescribed. Do not give EVAMIST to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about EVAMIST that is written for health professionals. For more information, go to www.Evamist.com or call Padagis ® at 1-866-634-9120. What are the ingredients in EVAMIST? Active ingredient: estradiol Inactive ingredients: octisalate, alcohol
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.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 clinical practice. In a 12-week, randomized, placebo-controlled trial of Evamist in 454 women, 80 to 90 percent of women randomized to active drug received at least 70 days of therapy and 75 to 85 percent randomized to placebo received at least 70 days of therapy. The adverse reactions that occurred in at least 5 percent of women in any treatment group are shown in Table 1. Table 1. Frequency of Adverse Reactions (≥5%) in Any Treatment Group in a Controlled Study of Evamist Frequency n (%) System Organ Class Preferred Term 1 Spray 2 Sprays 3 Sprays Placebo (N = 77) Evamist (N = 76) Placebo (N = 76) Evamist (N = 74) Placebo (N = 75) Evamist (N = 76) Reproductive System and Breast Disorders Breast tenderness 0 (0) 4 (5) 4 (5) 5 (7) 0 (0) 4 (5) Nipple pain 0 (0) 2 (3) 0 (0) 5 (7) 0 (0) 1 (1) Gastrointestinal Disorders Nausea 5 (7) 1 (1) 1 (1) 2 (3) 4 (5) 2 (3) Infections and Infestations Nasopharyngitis 1 (1) 4 (5) 2 (3) 3 (4) 1 (1) 1 (1) Musculoskeletal and Connective Tissue Disorders Back pain 1 (1) 2 (3) 2 (3) 4 (5) 1 (1) 2 (3) Arthralgia 1 (1) 1 (1) 4 (5) 1 (1) 0 (0) 3 (4) Nervous system Headache 4 (5) 7 (9) 5 (7) 9 (12) 7 (9) 8 (11) Application site reactions were reported in 3 out of 226 (1.3%) women treated with Evamist.
14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women In a 12-week, randomized, double-blind, placebo-controlled clinical trial, a total of 454 postmenopausal women (average 53 years of age, 70 percent Caucasian and 24 percent African-American) were randomized and received at least one dose of Evamist (one, two or three 90 mcL sprays) or placebo. Generally healthy postmenopausal women were enrolled with a mean total frequency of ≥56 moderate to severe vasomotor symptoms per week (≥8 per day). Efficacy was determined as a statistically significant and clinically significant (at least two per day or 14 per week difference) reduction in hot flush frequency and a statistically significant reduction in severity for Evamist versus placebo. One, two or three daily sprays of Evamist were shown to be better than placebo for relief of frequency (Table 3) and severity (Table 4) of moderate to severe vasomotor symptoms at Week 4 and Week 12. Table 3. Effect of Treatment on the Daily Frequency of Moderate to Severe Vasomotor Symptoms at Week 4 and Week 12 (Intent-To-Treat Population, LOCF) Mean Change from Baseline a (SD) Treatment (N) Baseline Mean (SD) Week 4 Mean (SD) Week 12 Mean (SD) 1 Spray Evamist (N=76) 11.81 (4.07) -6.26 (4.01) -8.10 (4.02) Placebo (N=77) 12.41 (5.59) -3.64 (5.30) -4.76 (5.84) Difference b — -2.62 -3.34 p-value c — 0.0010 0.0004 2 Sprays Evamist (N=74) 12.66 (7.33) -7.30 (6.93) -8.66 (6.65) Placebo (N=76) 12.13 (6.10) -4.74 (4.38) -6.19 (5.77) Difference b — -2.56 -2.47 p-value c — 0.0027 0.0099 3 Sprays Evamist (N=76) 10.78 (3.58) -6.64 (4.23) -8.44 (4.50) Placebo (N=75) 12.55 (11.94) -4.54 (7.40) -5.32 (6.30) Difference b — -2.10 -3.12 p-value c — 0.0002 <0.0001 a Mean change and difference based on raw data b Evamist versus placebo c Tests for pairwise differences using ANCOVA Table 4. Effect of Treatment on the Weekly Severity of Moderate to Severe Vasomotor Symptoms at Week 4 and Week 12 (Intent-To-Treat Population, LOCF) a Mean Change from Baseline b (SD) Treatment (N) Baseline Mean (SD) Week 4 Mean (SD) Week 12 Mean (SD) 1 Spray Evamist (N=76) 2.53 (0.25) -0.47 (0.80) -1.04 (1.01) Placebo (N=77) 2.55 (0.25) -0.19 (0.55) -0.26 (0.60) Difference c — -0.28 -0.78 p-value d — 0.0573 <0.0001 2 Sprays Evamist (N=74) 2.54 (0.21) -0.57 (0.83) -0.92 (1.01) Placebo (N=76) 2.54 (0.22) -0.25 (0.64) -0.54 (0.89) Difference c — -0.32 -0.38 p-value d — 0.0160 0.0406 3 Sprays Evamist (N=76) 2.58 (0.25) -0.43 (0.66) -1.07 (1.01) Placebo (N=75) 2.54 (0.24) -0.13 (0.53) -0.31 (0.75) Difference c — -0.30 -0.76 p-value d — 0.0031 <0.0001 a Severity score calculated as: (2 x number moderate + 3 x number severe) / (number moderate + number severe) b Mean change and difference based on raw data c Evamist versus placebo d Tests for pairwise differences using ANCOVA 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 cause. 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 years of age; 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 5. Table 5. Relative and Absolute Risk Seen in the Estrogen Alone Substudy of WHI a Event Relative Risk CE vs. Placebo (95% nCI b ) CE (n = 5,310) Placebo (n = 5,429) Absolute Risk per 10,000 Women-Years CHD events c Non-fatal MI c CHD death c CHD death c 0.95 (0.78-1.16) 0.91 (0.73-1.14) 1.01 (0.71-1.43) 54 40 16 57 43 16 All strokes c Ischemic stroke c 1.33 (1.05-1.68) 1.55 (1.19-2.01) 45 38 33 25 Deep vein thrombosis c,d 1.47 (1.06-2.06) 23 15 Pulmonary embolism c 1.37 (0.90-2.07) 14 10 Invasive breast cancer c 0.80 (0.62-1.04) 28 34 Colorectal cancer e 1.08 (0.75-1.55) 17 16 Hip fracture c 0.65 (0.45-0.94) 12 19 Vertebral fractures c,d 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures c,d 0.58 (0.47-0.72) 35 59 Total fractures c,d 0.71 (0.64-0.80) 144 197 Death due to other causes e,f 1.08 (0.88-1.32) 53 50 Overall mortality c,d 1.04 (0.88-1.22) 79 75 Global index g 1.02 (0.92-1.13) 206 201 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. d Not included in “global index”. e Results are based on an average follow-up of 6.8 years. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 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 to 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 differences in distribution of stroke subtypes 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, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. 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 reduction 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 years of age: 83.9 percent White, 6.5 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a,b Event Relative Risk CE/MPA vs. Placebo (95% nCI c ) CE/MPA (n = 8,506) Placebo (n = 8,102) Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death c CHD death c 1.23 (0.99-1.53) 1.28 (1.00-1.63) 1.10 (0.70-1.75) 41 31 8 34 25 8 All strokes Ischemic stroke 1.31 (1.03-1.68) 1.44 (1.09-1.90) 33 26 25 18 Deep vein thrombosis d 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer e 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer d 0.81 (0.48-1.36) 6 7 Cervical cancer d 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures d 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59-0.85) 44 62 Total fractures d 0.76 (0.69-0.83) 152 199 Overall mortality f 1.00 (0.83-1.19) 52 52 Global index g 1.13 (1.02-1.25) 184 165 a Adapted from numerous WHI publications, WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 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, 0.44-1.07)]. 14.3 Women’s Health Initiative Memory Study The WHIMS estrogen-alone ancillary study of the WHI, enrolled 2,947 predominantly 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, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) 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, 0.83-2.66). 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 type (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 ( 5.3 ) 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 of age, and 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, 1.12-3.48). 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 type (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 ( 5.3 ) 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, 1.19-2.60). 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 ( 5.3 ) and Use in Specific Populations ( 8.5 )] .
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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 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA . 2007:297;1465-1477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med . 2006;166:357–365. 3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med . 2006;166:772-780. 4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA . 2004:292;1573-1580. 5. 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. 6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA . 2003:289;3234-3253. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin in Gynecologic Cancers and Associated Diagnostic Procedures. JAMA . 2003:290;1739-1748. 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA . 2004:291;2947-2958. 9. 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. 10. 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 Evamist to determine whether those over 65 years of age differ from younger subjects in their response to Evamist. 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 ( 5.3 ), and Clinical Studies ( 14.3 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )].
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 Evamist is not indicated for use in pediatric patients. 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 Risk Summary Evamist is not indicated for use in pregnancy. There are no data with the use of Evamist 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.
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 8.1 Pregnancy Risk Summary Evamist is not indicated for use in pregnancy. There are no data with the use of Evamist 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 breast-feeding females. 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 Evamist and any potential adverse effects on the breastfed child from Evamist or from the underlying maternal condition. 8.4 Pediatric Use Evamist 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 Evamist to determine whether those over 65 years of age differ from younger subjects in their response to Evamist. 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 ( 5.3 ), and Clinical Studies ( 14.3 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )].
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 Evamist (NDC 0574-2067-27) is supplied as a homogeneous solution of estradiol USP, octisalate USP and alcohol USP. The liquid formulation of Evamist is packaged in a glass vial fitted with a metered-dose pump. The unit is encased in a plastic housing with a conical bell opening that controls the distance, angle, and area of application of the metered-dose spray. Each metered-dose pump contains 8.1 mL and is designed to deliver 56 sprays of 90 mcL after priming. One spray contains 1.53 mg estradiol. 16.2 Storage and Handling Keep out of reach of children. Alcohol and alcohol-based liquids are flammable. Avoid fire, flame or smoking until the spray has dried. Store at room temperature 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F). Do not freeze.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and UNINTENTIONAL SECONDARY EXPOSURE TO ESTROGEN 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 progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed and random endometrial sampling when indicated, to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Cardiovascular Disorders and Probable Dementia 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 ( 5.1 ), 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 and 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 ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.3 )]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.2 , 14.3 )]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone 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. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens 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 The WHI estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), DVT, 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 ( 5.1 ), and Clinical Studies ( 14.2 )] . The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.3 )] . Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warning and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.2 )] . Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions ( 5.2 ), and Clinical Studies ( 14.2 )] . Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen 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. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Unintentional Secondary Exposure Breast budding and breast masses in prepubertal females and gynecomastia and breast masses in prepubertal males have been reported following unintentional secondary exposure to Evamist by women using this product. In most cases, the condition resolved with removal of Evamist exposure. Women should ensure that children do not come into contact with the site(s) where Evamist is applied. Healthcare providers should advise patients to strictly adhere to recommended instructions for use [see Warnings and Precautions ( 5.4 )] . WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and UNINTENTIONAL SECONDARY EXPOSURE TO ESTROGEN 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 ( 5.2 ) • The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 5.1 ) • 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 ( 5.3 ) • Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) Estrogen Plus Progestin Therapy • The WHI estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), DVT, stroke, and myocardial infarction (MI) ( 5.1 ) • The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.2 ) • 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 ( 5.3 ) • Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) Unintentional Secondary Exposure • Breast budding, breast masses, and gynecomastia have been reported in children following unintentional secondary exposure to Evamist ( 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