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| Product NDC Code | 45802-310 | ||||
|---|---|---|---|---|---|
| Drug Name | Estradiol |
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| Type | Generic | ||||
| Pharm Class | Estradiol Congeners [CS], Estrogen Receptor Agonists [MoA], Estrogen [EPC] |
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| Route | TOPICAL | ||||
| Dosage Form | GEL | ||||
| RxCUI drug identifier | 2619677, 2619679, 2619681, 2619683, 2619685 |
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| Application Number | ANDA216524 | ||||
| Labeler Name | Padagis Israel Pharmaceuticals Ltd | ||||
| Packages |
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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 and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of estradiol gel 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 (incidence >5 percent and greater than placebo) in any estradiol gel treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact 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 practice. Estradiol gel was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse reactions that occurred at a rate greater than 5 percent and greater than placebo in any of the treatment groups are summarized in Table 1. Table 1: Number (%) of Subjects with Common Adverse Reactions* in a 12-Week Placebo-Controlled Study of Estradiol Gel Estradiol Gel Placebo SYSTEM ORGAN CLASS Preferred Term 0.25 grams/day N=122 n (%) 0.5 grams/day N=123 n (%) 1.0 gram/day N=125 n (%) N=125 n (%) INFECTIONS & INFESTATIONS Nasopharyngitis 7 (5.7) 5 (4.1) 6 (4.8) 5 (4.0) Upper Respiratory Tract Infection 7 (5.7) 3 (2.4) 2 (1.6) 2 (1.6) Vaginal mycosis 1 (0.8) 3 (2.4) 8 (6.4) 4 (3.2) REPRODUCTIVE SYSTEM & BREAST DISORDERS Breast Tenderness 3 (2.5) 7 (5.7) 11 (8.8) 2 (1.6) Metrorrhagia 5 (4.1) 7 (5.7) 12 (9.6) 2 (1.6) *Adverse reactions reported by >5 percent of patients in any treatment group. In a 12-week placebo-controlled study of estradiol gel, application site reactions were seen in <1 percent of participating women. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of estradiol gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Amenorrhea, dysmenorrhea, ovarian cyst, vaginal discharge Breasts Gynecomastia Cardiovascular Palpitations, ventricular extrasystoles Gastrointestinal Flatulence Skin Rash pruritic, urticaria Eyes Retinal vein occlusion Central Nervous System Tremor Miscellaneous Arthralgia, application site rash, asthenia, chest discomfort, fatigue, feeling abnormal, heart rate increased, insomnia, malaise, muscle spasms, pain in extremity, weight increased
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 In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and result in adverse reactions. • Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration ( 7 ).
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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. 12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to estradiol gel 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 Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, estradiol gel demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC 0-24 and C max following once daily dosing to the skin of either the right or left upper thigh (Table 2). Table 2: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Estradiol Gel 0.1% Parameter (units) Estradiol Gel 0.25 grams Estradiol Gel 0.5 grams Estradiol Gel 1.0 gram AUC 0-24 (pg•h/mL) 236 (94) 504 (149) 732 (81) C max (pg/mL) 14.7 (84) 28.4 (139) 51.5 (86) C avg (pg/mL) 9.8 (92) 21 (148) 30.5 (81) t max * (h) 16 (0, 72) 10 (0, 72) 8 (0, 48) E2:E1 ratio 0.42 0.65 0.65 *Median (Min, Max). Steady-state serum concentration of estradiol are achieved by day 12 following daily application of estradiol gel to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1. Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of Estradiol Gel 0.1% The effect of sunscreens and other topical lotions on the systemic exposure of estradiol gel has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. 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 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. Although the clinical significance has not been determined , estradiol from estradiol gel does not undergo first pass metabolism and provides estradiol to estrone ratios at steady state in the range of 0.42 to 0.65. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of estradiol gel. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 gram of estradiol gel (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh-to-arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive. Effects of Washing The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 gram of estradiol gel to a 200 cm 2 area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin and resulted in a 30 to 38 percent decrease in the mean total 24-hour exposure to 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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
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 estradiol gel 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 Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, estradiol gel demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC 0-24 and C max following once daily dosing to the skin of either the right or left upper thigh (Table 2). Table 2: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of Estradiol Gel 0.1% Parameter (units) Estradiol Gel 0.25 grams Estradiol Gel 0.5 grams Estradiol Gel 1.0 gram AUC 0-24 (pg•h/mL) 236 (94) 504 (149) 732 (81) C max (pg/mL) 14.7 (84) 28.4 (139) 51.5 (86) C avg (pg/mL) 9.8 (92) 21 (148) 30.5 (81) t max * (h) 16 (0, 72) 10 (0, 72) 8 (0, 48) E2:E1 ratio 0.42 0.65 0.65 *Median (Min, Max). Steady-state serum concentration of estradiol are achieved by day 12 following daily application of estradiol gel to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1. Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of Estradiol Gel 0.1% The effect of sunscreens and other topical lotions on the systemic exposure of estradiol gel has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. 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 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. Although the clinical significance has not been determined , estradiol from estradiol gel does not undergo first pass metabolism and provides estradiol to estrone ratios at steady state in the range of 0.42 to 0.65. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of estradiol gel. Potential for Estradiol Transfer The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 gram of estradiol gel (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh-to-arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive. Effects of Washing The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 gram of estradiol gel to a 200 cm 2 area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin and resulted in a 30 to 38 percent decrease in the mean total 24-hour exposure to 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 Estradiol gel is contraindicated in women with any of the following conditions: • Undiagnosed abnormal genital bleeding [see Warning and Precautions ( 5.2 )] • Breast cancer or history of breast cancer [see Warning and Precautions ( 5.2 )] • Estrogen-dependent neoplasia [see Warning and Precautions ( 5.2 )] • Active DVT, PE, or history of these conditions [see Warning and Precautions ( 5.1 )] • Active arterial thromboembolic disease (e.g., stroke and MI), or a history of these conditions [see Warning and Precautions ( 5.1 )] • Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel • Hepatic impairment or disease • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders • Undiagnosed abnormal genital bleeding ( 4 ) • Breast cancer or a history of breast cancer ( 4 , 5.2 ) • Estrogen-dependent neoplasia ( 4 , 5.2 ) • Active DVT, PE, or history of these conditions ( 4 , 5.1 ) • Active arterial thromboembolic disease (e.g., stroke and MI), or history of these conditions ( 4 , 5.1 ) • Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol gel ( 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 Estradiol gel 0.1 percent, is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm 2 ) of the thigh in a thin layer. Estradiol gel is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for topical application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). The active component of the topical gel is estradiol. Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. It has an empirical formula of C 18 H 24 O 2 and molecular weight of 272.39. The structural formula is: The remaining components of the gel (carbomer, ethanol (62.03% v/v), propylene glycol, purified water, and triethanolamine) are pharmacologically inactive. estradiol chemical structure
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 a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions ( 5.2 , 5.14 )] . Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. Daily administration of 0.25 to 1.25 grams of estradiol gel to the right or left upper thigh on alternating days. Women should be started with the lowest effective dose and the dose should be evaluated periodically ( 2 ). 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with the 0.25 grams applied once daily on the skin of either the right or left upper thigh. Adjust the dose up to a maximum of 1.25 grams, as needed. The application surface area should be about 5 by 7 inches (approximately the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, apply estradiol gel to the right or left upper thigh on alternating days. Do not apply estradiol gel on the face, breasts, or irritated skin or in or around the vagina. Allow gel to dry after application before dressing. Do not wash the application site within 1 hour after applying estradiol gel. Avoid contact of the gel with eyes. Wash hands after application.
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 gel is available in five doses of 0.25, 0.5, 0.75, 1.0, and 1.25 grams for transdermal application (corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively). Estradiol gel is a clear, colorless gel, which is odorless when dry. Gel: 0.25, 0.5, 0.75, 1.0, and 1.25 gram-filled single-dose foil packets containing 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively ( 3 )
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 gel 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.ESTRADIOL estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL TROLAMINE WATER ESTRADIOL estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL TROLAMINE WATER ESTRADIOL estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL TROLAMINE WATER ESTRADIOL estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL TROLAMINE WATER ESTRADIOL estradiol ESTRADIOL ESTRADIOL CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) ALCOHOL PROPYLENE GLYCOL TROLAMINE WATER
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, and 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, and 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.PRINCIPAL DISPLAY PANEL – 0.25 mg Packet Carton NDC 45802-134-30 Rx Only Estradiol Gel, 0.1% 0.25 mg 30 packets 0.25 g gel provides 0.25 mg estradiol gel/packet The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. 0.25mg carton serialization template
PRINCIPAL DISPLAY PANEL – 0.5 mg Packet Carton NDC 45802-202-30 Rx Only Estradiol Gel, 0.1% 0.5 mg 30 packets 0.5 g gel provides 0.5 mg estradiol/packet The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. 0.5mg carton serialization template
PRINCIPAL DISPLAY PANEL – 0.75 mg Packet Carton NDC 45802-310-30 Rx Only Estradiol Gel, 0.1% 0.75 mg 30 packets 0.75 g gel provides 0.75 mg estradiol/packet The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. 0.75mg carton serialization template
PRINCIPAL DISPLAY PANEL – 1.0 mg Packet Carton NDC 45802-452-30 Rx Only Estradiol Gel, 0.1% 1 mg 30 packets 1 g gel provides 1 mg estradiol/packet The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. 1mg carton serialization template
PRINCIPAL DISPLAY PANEL – 1.25 mg Packet Carton NDC 45802-573-30 Estradiol Gel, 0.1% 1.25 mg 30 packets 1.25 g gel provides 1.25 mg estradiol/packet The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. 1.25mg carton serialization template
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.Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 11/2023
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 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 Estradiol Gel Inform women about the possibility of secondary exposure to estradiol gel: • Apply estradiol gel as directed and keep children from contacting exposed application site(s). If direct contact with the application site occurs, wash the contact area thoroughly with soap and water. • 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: • Have the child(ren) evaluated by a healthcare provider. • Have women contact their healthcare provider to discuss the appropriate use and handling of estradiol gel when around children. • Pets may also be unintentionally exposed to estradiol gel if above precautions are not followed. 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 ( 5.1 , 5.2 , 5.3 )] . 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 headaches, breast pain and tenderness, nausea and vomiting. Manufactured by Padagis ® Yeruham, Israel www.padagis.com Rev 02-24 97S00 RC PH4
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.Patient Information PATIENT INFORMATION Estradiol (es-tra-DYE-ole) Gel, 0.1% Read this Patient Information leaflet before you start using estradiol gel 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 ESTRADIOL GEL (AN ESTROGEN HORMONE)? • Using estrogen-alone increases your chance of getting cancer of the uterus (womb). • Report any unusual vaginal bleeding right away while you are using estradiol gel. 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 and older • Do not use estrogens with progestogens to prevent heart disease, heart attacks, 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 of age or older • 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 estradiol gel will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol gel. What is estradiol gel? Estradiol gel is a prescription medicine that contains estradiol (an estrogen hormone). Estradiol gel is a clear, colorless, smooth gel that is odorless when dry. When applied to the skin, estradiol is absorbed through the skin into the bloodstream. What is estradiol gel used for? Estradiol gel 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 to 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 develop 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 estrogens. In other women, symptoms can be more severe. Who should not use estradiol gel? Do not start using estradiol gel 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. • have been diagnosed with a bleeding disorder • 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 (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol gel. • had a stroke or heart attack • currently have or have had blood clots • currently have or have had liver problems • are allergic to estradiol gel or any of its ingredients See the list of ingredients in estradiol gel at the end of this leaflet. Before you use estradiol gel, 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 unusual vaginal bleeding to find out the cause. • have any other medical conditions that may become worse while you are using estradiol gel Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraines, endometriosis, lupus, angioedema (swelling of face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • are going to have surgery or will be on bedrest Your healthcare provider will let you know if you need to stop using estradiol gel. • are pregnant or think you may be pregnant Estradiol gel is not for pregnant women. • are breastfeeding The hormone in estradiol gel 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 estradiol gel works. Estradiol gel may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should I use estradiol gel? • 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 and 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 gel. How should estradiol gel be applied? • Estradiol gel should be applied 1-time a day, around the same time each day. • Apply estradiol gel to clean, dry, and unbroken (without cuts or scrapes) skin. If you take a bath or shower, be sure to apply your estradiol gel after your skin is dry. The application site should be completely dry before dressing or swimming. • Apply estradiol gel to either your left or right upper thigh. Change between your left and right upper thigh each day to help prevent skin irritation. TO APPLY: Step 1: Wash and dry your hands thoroughly. Step 2: Sit in a comfortable position. Step 3: Cut or tear the estradiol gel packet as shown in Figure A. Figure A Step 4: Using your thumb and pointer (index) finger, squeeze the entire contents of the estradiol gel packet onto the skin of the upper thigh as shown in Figure B. Figure B Step 5: Gently spread the gel in a thin layer on your upper thigh over an area of about 5 by 7 inches, or two palm prints as shown in Figure C. It is not necessary to massage or rub in estradiol gel. Figure C Step 6: Allow the gel to dry completely before dressing. Step 7: Throw away (dispose) of the empty estradiol gel packet in the trash. Step 8: Wash your hands with soap and water immediately after applying estradiol gel to remove any remaining gel and reduce the chance of transferring estradiol gel to other people. Important things to remember when using estradiol gel • Allow the gel to dry before dressing. Try to keep the area dry for as long as possible. • Do not allow another person to come in contact with the area of skin where you applied the gel for at least 1 hour after you apply estradiol gel. • You should not have another person to apply the gel for you. However, if you need to have another person help you, have that person wear a disposable plastic glove to avoid direct contact with estradiol gel. • Do not apply estradiol gel to your face, breast, or irritated skin. • Never apply estradiol gel in or around the vagina. • Estradiol gel contains alcohol. Alcohol based gels are flammable. Avoid fire, flame or smoking until the gel has dried. What should I do if I miss a dose? If you miss a dose, do not double the dose on the next day to catch up. If your next dose is less than 12 hours away, it is best just to wait and apply your normal dose the next day. If it is more than 12 hours until the next dose, apply the dose you missed and resume your normal dosing the next day. Do not apply estradiol gel more than 1-time each day. If you accidentally spill some of the contents of a estradiol gel packet, do not open a new estradiol gel packet. Wait and apply your normal dose the next day. What should I do if someone else is exposed to estradiol gel? To reduce the chance of transfer to another person (or pet) let the estradiol gel dry completely. Wash your hands with soap and water after application. If someone else is exposed to estradiol gel by direct contact with the wet gel, have that person wash the area of contact with soap and water right away. This is especially important for men and children. The longer the gel is in contact with the skin before washing, the greater the chance that the other person (or pet) will absorb some of the estrogen hormone. This may harm them. In case of any signs or symptoms of estrogen exposure in the other person (or pet), contact your healthcare provider (or veterinarian, if appropriate). What should I do if I get estradiol gel in my eyes? If you get estradiol gel in your eyes, flush your eyes right away with lukewarm tap water. If you have concerns, contact your healthcare provider. What are the possible side effects of estradiol gel? 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 • high or low blood calcium (hypercalcemia) • gall bladder disease • visual abnormalities • high blood pressure • high levels of fat (triglycerides) in your blood • liver problems • changes in your thyroid hormone levels • fluid retention • cancer change of endometriosis • enlargement of benign tumors of the uterus (“fibroids”) • worsening swelling of face and tongue (angioedema) • changes in certain laboratory test results such as high blood sugar 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 • swelling of face, lips, and tongue with or without red, itchy bumps The most common side effects of estradiol gel include: • irregular vaginal bleeding or spotting • breast tenderness • vaginal yeast infection • upper respiratory tract (nose, sinuses, pharynx or larynx) infection These are not all the possible side effects of estradiol gel. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have any side effects that bother you or do not go away. You may report side effects to FDA at 1-800-FDA-1088 or Padagis ® at 1-866-634-9120. What can I do to lower my chances of a serious side effect with estradiol gel? • Talk with your healthcare provider regularly about whether you should continue using estradiol gel. • If you have a uterus, talk to your healthcare provider about whether the addition of a progestogen is right for you. • In general, the addition of a progestogen is recommended for a woman 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 estradiol gel. • 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 of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. How should I store estradiol gel? Store estradiol gel packets at room temperature, 68 to 77°F (20 to 25°C). Keep estradiol gel and all medicines out of the reach of children. General information about safe and effective use of estradiol gel Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use estradiol gel for a condition for which it was not prescribed. Do not give estradiol gel to other people, even if they have the same symptoms that you have. It may harm them. This leaflet provides a summary of the most important information about estradiol gel. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about estradiol gel that is written for health professionals. What are the ingredients in estradiol gel? Active ingredient: estradiol. Inactive ingredients: carbomer, ethanol (62.03% v/v), propylene glycol, purified water, and triethanolamine. How is estradiol gel supplied? Estradiol gel is supplied in individual foil packets, each one containing a single day's dose. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured by Padagis ® Yeruham, Israel www.padagis.com Rev 02-24 97S00 RC PH4 Figure A Figure B Figure C
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 Vasomotor Symptoms in Postmenopausal Women A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of estradiol gel for vasomotor symptoms in 495 postmenopausal women (86.5 percent White; 10.1 percent Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2-week period prior to treatment). Women applied placebo, estradiol gel 0.25 grams (0.25 mg estradiol), estradiol gel 0.5 grams (0.5 mg estradiol) or estradiol gel 1.0 gram (1.0 mg estradiol) once daily to the thigh. Reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes were statistically significant for the 0.5 grams per day and the 1.0 gram per day estradiol gel doses when compared to placebo at week 4. Statistically significant reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes for the estradiol gel 0.25 grams per day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in median daily frequency and severity of hot flushes for all three estradiol gel doses (0.25 grams per day, 0.5 grams per day and 1.0 gram per day) compared to placebo at week 12. See Table 3 for results. Table 3: Summary of Change From Baseline in the Median Daily Frequency and Severity of Hot Flushes during Estradiol Gel Treatment (ITT Population) Estradiol Gel Placebo Evaluation 0.25 grams/day N=121 0.5 grams/day N=119 1.0 gram/day N=124 N=124 Frequency of Daily Hot Flushes Baseline Median 9.72 9.24 9.64 9.32 Median Change: Week 4 p-value † -5.00 0.132 -5.73 0.011 -7.20 <0.001 -3.63 Median Change: Week 7 p-value † -6.62 <0.001 -7.14 <0.001 -7.71 <0.001 -4.37 Median Change: Week 12 p-value † -6.88 <0.001 -7.29 <0.001 -8.35 <0.001 -4.48 Severity of Daily Hot Flushes Baseline Median 2.52 2.51 2.52 2.54 Median Change: Week 4 p-value † -0.07 0.283 -0.18 <0.001 -0.47 <0.001 -0.04 Median Change: Week 7 p-value † -0.24 <0.001 -0.46 <0.001 -1.06 <0.001 -0.06 Median Change: Week 12 p-value † -0.33 0.021 -0.56 0.002 -1.69 <0.001 -0.13 † p-values from the van Elteren’s test stratified by pooled center; comparison in median change was significant if p<0.05. 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; 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 a Event Relative Risk CE vs. Placebo (95% nCl b ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events c Nonfatal MI 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 1.33 (1.05 – 1.68) 45 33 Ischemic stroke c 1.55 (1.19 – 2.01) 38 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 (0.91 – 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, pulmonary embolism, 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 nonsignificant 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. See Table 4. 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, 0.36–1.09)] 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 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 a,b Event c Relative Risk CE/MPA vs. Placebo (95% nCl c ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events Nonfatal MI CHD death 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 1.31 (1.03 – 1.68) 33 25 Ischemic stroke 1.44 (1.09 – 1.90) 26 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, pulmonary embolism, 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 for 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 WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (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)-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, 0.83–2.66). 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 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 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, 1.21–3.48). 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 )] .
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 on 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 studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.2 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions ( 5.1 , 5.2 ) and Clinical Studies ( 14.2 )] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies ( 14.3 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] .
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 gel 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 Estradiol gel is not indicated for use in pregnant women. There are no data with the use of estradiol gel in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
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 Estradiol gel is not indicated for use in pregnant women. There are no data with the use of estradiol gel in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol gel and any potential adverse effects on the breastfed child from estradiol gel or from the underlying maternal condition. 8.4 Pediatric Use Estradiol gel is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in studies utilizing estradiol gel to determine whether those over 65 years of age differ from younger subjects in their response to estradiol gel. The Women's Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.2 )] . In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions ( 5.1 , 5.2 ) and Clinical Studies ( 14.2 )] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies ( 14.3 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.3 )] .
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 Gel, 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, 0.75, 1.0, and 1.25 grams, corresponding to 0.25, 0.5, 0.75, 1.0, and 1.25 mg estradiol, respectively. NDC 45802-134-30, carton of 30 packets, 0.25 mg estradiol per single-dose foil packet NDC 45802-202-30, carton of 30 packets, 0.5 mg estradiol per single-dose foil packet NDC 45802-310-30, carton of 30 packets, 0.75 mg estradiol per single-dose foil packet NDC 45802-452-30, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet NDC 45802-573-30, carton of 30 packets, 1.25 mg estradiol per single-dose foil packet Keep out of the reach of children. 16.2 Storage and Handling Store at 20 to 25°C (68 to 77°F). Excursions permitted to 15 to 30°C (59 to 86°F). [See USP Controlled Room Temperature.]
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 and BREAST CANCER 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 or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with 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 the 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 (0.625 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 ( 5.3 ), 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 Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.2 , 14.3 )] . 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. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA and BREAST CANCER 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 study 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 )
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