ENJUVIA- synthetic conjugated estrogens, b tablet, film coated
Teva Women's Health, Inc.
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ENJUVIA safely and effectively. See full prescribing information for ENJUVIA.
ENJUVIA® (synthetic conjugated estrogens, B) Tablets for oral use Initial U.S. Approval: 2004 WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIASee full prescribing information for complete boxed warning.Estrogen-alone Therapy
Estrogen Plus Progestin Therapy
RECENT MAJOR CHANGESINDICATIONS AND USAGEENJUVIA (synthetic conjugated estrogens, B) is a mixture of estrogens indicated for:
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONSADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 10/2015 |
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].
Cardiovascular Disorders and Probable Dementia
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3),and Clinical Studies (14.3, 14.4)].
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 (14.3)].
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.4)].
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.
Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.3, 14.4)].
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1),and Clinical Studies (14.3)].
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.4)].
Breast Cancer
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.3)].
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins.
Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Limitation of Use
When prescribing solely for the treatment of moderate to severe vaginal dryness and pain with intercourse, topical vaginal products should be considered.
Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer [see Boxed Warning].
A woman without a uterus does not need progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [seeWarnings and Precautions (5.2, 5.14)].
Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary.
ENJUVIA therapy consists of a single tablet taken orally once daily.
Women should be started at the lowest approved dose of 0.3 mg ENJUVIA daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider.
ENJUVIA therapy consists of a single tablet taken orally once daily.
When prescribing solely for the treatment of moderate to severe vaginal dryness and pain during intercourse, topical vaginal products should be considered.
ENJUVIA is available as tablets in 0.3 mg, 0.45 mg 0.625 mg, 0.9 mg, and 1.25 mg strengths.
ENJUVIA therapy is contraindicated in women with any of the following conditions:
An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
Stroke
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [seeClinical Studies (14.3)]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 woman-years).1
In the WHI estrogen-plus-progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [seeClinical Studies (14.3)]. The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
Coronary Heart Disease
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2[see Clinical Studies (14.3)].
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.3)].
In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall.
Venous Thromboembolism
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years3[seeClinical Studies (14.3)]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4[seeClinical Studies (14.3)]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Breast Cancer
The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80)5[seeClinical Studies (14.3)].
The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo6[seeClinical Studies (14.3)]. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade, and hormone receptor status did not differ between the groups [seeClinical Studies (14.3)].
Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
Ovarian Cancer
The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association.
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. 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-years8[seeUse in Specific Populations (8.5), and Clinical Studies (14.4)].
In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
After an average follow-up of four years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. 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 cases per 10,000 women-years8[seeUse in Specific Populations (8.5), and Clinical Studies (14.4)].
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies 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). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8[seeUse in Specific Populations (8.5), and Clinical Studies (14.4)].
A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.
In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogen-alone is prescribed.
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In a 12-week clinical trial, 209 postmenopausal women with vasomotor symptoms were treated with ENJUVIA. Adverse reactions that occurred in the study at a rate greater than or equal to 3% and greater than placebo are summarized in Table 1.
Body System/Adverse Reaction | 0.3 mg
n=68 | 0.625 mg
n=72 | 1.25 mg
n=69 | Placebo
n=72 |
---|---|---|---|---|
Number of Patients in Safety Sample (%) |
68 (100) |
72 (100) |
69 (100) |
72 (100) |
Number of Patients with Adverse Reactions (%) |
49 (72) |
55 (76) |
56 (81) |
51 (71) |
Number of Patients without Adverse Reactions (%) |
19 (28) |
17 (24) |
13 (19) |
21 (29) |
Body as a Whole | ||||
Abdominal Pain |
3 (4) |
11 (15) |
3 (4) |
7 (10) |
Accidental Injury |
6 (9) |
2 (3) |
3 (4) |
5 (7) |
Asthenia |
2 (3) |
3 (4) |
2 (3) |
0 |
Chest Pain |
2 (3) |
3 (4) |
0 |
0 |
Chills |
0 |
3 (4) |
1 (1) |
1 (1) |
Flu Syndrome |
4 (6) |
3 (4) |
5 (7) |
3 (4) |
Headache |
10 (15) |
18 (25) |
11 (16) |
15 (21) |
Pain |
10 (15) |
14 (19) |
7 (10) |
6 (8) |
Digestive System | ||||
Constipation |
3 (4) |
2 (3) |
1 (1) |
2 (3) |
Diarrhea |
4 (6) |
2 (3) |
3 (4) |
4 (6) |
Flatulence |
3 (4) |
5 (7) |
3 (4) |
2 (3) |
Nausea |
5 (7) |
7 (10) |
8 (12) |
6 (8) |
Metabolic and Nutritional Disorders | ||||
Peripheral Edema |
1 (2) |
3 (4) |
3 (4) |
2 (3) |
Nervous System | ||||
Depression |
2 (3) |
3 (4) |
1 (1) |
1 (1) |
Dizziness |
5 (7) |
3 (4) |
1 (1) |
3 (4) |
Emotional Lability |
2 (3) |
3 (4) |
1 (1) |
1 (1) |
Paresthesia |
0 |
4 (6) |
1 (1) |
0 |
Respiratory System | ||||
Bronchitis |
0 |
3 (4) |
5 (7) |
3 (4) |
Cough Increased |
1 (2) |
2 (3) |
3 (4) |
2 (3) |
Pharyngitis |
3 (4) |
2 (3) |
0 |
0 |
Rhinitis |
3 (4) |
4 (6) |
5 (7) |
4 (6) |
Sinusitis |
2 (3) |
3 (4) |
5 (7) |
2 (3) |
Skin and Appendages | ||||
Acne |
0 |
3 (4) |
1 (1) |
0 |
Fungal Dermatitis |
1 (2) |
0 |
3 (4) |
1 (1) |
Pruritus |
2 (3) |
2 (3) |
4 (6) |
3 (4) |
Urogenital System | ||||
Breast Pain |
0 |
9 (13) |
10 (15) |
3 (4) |
Dysmenorrhea |
1 (2) |
6 (8) |
1 (1) |
2 (3) |
Vaginitis |
1 (2) |
5 (7) |
2 (3) |
3 (4) |
In a second 12-week clinical trial, 310 women with symptoms of vulvar and vaginal atrophy were treated (154 women with ENJUVIA 0.3 mg tablets and 156 women with placebo). Adverse reactions that occurred in the study at a rate greater than or equal to 3% and greater than placebo are summarized in Table 2.
Body System/Adverse Reaction | 0.3 mg
n=154 | Placebo
n=156 |
---|---|---|
Number of Patients in Safety Sample (%) |
154 (100) |
156 (100) |
Number of Patients with Adverse Reactions (%) |
83 (54) |
74 (47) |
Number of Patients without Adverse Reactions (%) |
71 (46) |
82 (53) |
Infections and Infestations | ||
Upper Respiratory Tract Infection |
6 (4) |
4 (3) |
Sinusitis |
5 (3) |
2 (1) |
Reproductive System and Breast Disorders | ||
Breast Tenderness |
6 (4) |
1 (1) |
Musculoskeletal and Connective Tissue Disorders | ||
Back Pain |
6 (4) |
2 (1) |
The following adverse reactions have been identified during post-approval use of ENJUVIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: abdominal discomfort, abdominal distension, nausea
Immune System Disorders: anaphylactic reaction, hypersensitivity
Musculoskeletal and connective tissue disorders: muscle spasms
Nervous System Disorders: headache, dizziness
Psychiatric disorders: insomnia
Reproductive system and Breast Disorders: breast pain, breast tenderness
Skin and Subcutaneous Tissue Disorders: alopecia, rash, urticaria
Vascular Disorders: deep vein thrombosis, thrombosis
No drug-drug interaction studies have been conducted with ENJUVIA.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.
ENJUVIA should not be used during pregnancy [seeContraindications (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
ENJUVIA should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen-alone therapy. Caution should be exercised when ENJUVIA is administered to a nursing woman.
ENJUVIA is not indicated in children. Clinical studies have not been conducted in the pediatric population.
There have not been sufficient numbers of geriatric women involved in studies utilizing ENJUVIA to determine whether those over 65 years of age differ from younger subjects in their response to ENJUVIA.
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 [seeClinical Studies (14.3)].
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 [seeClinical Studies (14.3)].
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 [seeWarnings and Precautions (5.3), andClinical Studies (14.4)].
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8[seeWarnings and Precautions (5.3), and Clinical Studies (14.4)].
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 ENJUVIA therapy with institution of appropriate symptomatic care.
ENJUVIA (synthetic conjugated estrogens, B) tablets contain a blend of ten (10) synthetic estrogenic substances. The estrogenic substances are: sodium estrone sulfate, sodium equilin sulfate, sodium 17α-dihydroequilin sulfate, sodium 17α-estradiol sulfate, sodium 17β-dihydroequilin sulfate, sodium 17α-dihydroequilenin sulfate, sodium 17β‑dihydroequilenin sulfate, sodium equilenin sulfate, sodium 17β-estradiol sulfate, and sodium Δ8,9-dehydroestrone sulfate.
The structural formulae for these estrogens are:
ENJUVIA tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of synthetic conjugated estrogens, B. These tablets contain the following inactive ingredients: ascorbyl palmitate, butylated hydroxyanisole, colloidal silicon dioxide, edetate disodium dehydrate, plasticized ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, purified water, iron oxide red, titanium dioxide, polyethylene glycol, polysorbate 80, triacetate and triacetin/glycerol. In addition, the 0.45 mg tablets contain iron oxide black and iron oxide yellow; the 0.9 mg tablets also contain D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake, and FD&C yellow no. 6 aluminum lake; and the 1.25 mg tablets contain iron oxide yellow.
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 in postmenopausal women.
Absorption
Synthetic conjugated estrogens, B are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. ENJUVIA tablets release synthetic conjugated estrogens, B slowly over a period of several hours. Table 3 and Table 4 summarize the mean pharmacokinetic parameters for unconjugated (free) and conjugated (total) estrogens following single administration of two 0.625 mg tablets to 21 healthy postmenopausal women under fasting conditions. The effect of food on the bioavailability of synthetic conjugated estrogens, B following administration of ENJUVIA tablets has not been studied. However, the presence of food did not significantly affect the pharmacokinetics of a similar formulation of synthetic conjugated estrogens, B.
Cmax
(pg/mL) | tmax
(hr) | t½
(hr) | AUC0-48h
(pg•hr/mL) |
|
---|---|---|---|---|
Baseline-corrected estrone (% CV) |
75.87 (39) |
9.29 (25) |
23.46 (59) |
1601.59 (41) |
Equilin (% CV) |
41.94 (49) |
8.38 (27) |
15.09 (55) |
707.21 (46) |
Cmax = peak plasma concentration; tmax = time peak concentration occurs; t1/2 = apparent terminal-phase disposition half-life; AUC0-48h = total area under the concentration-time curve from time zero to time of last quantifiable concentration (48h); * Δ8,9 Dehydroestrone (free) levels were below the assay limit of quantitation; CV= Coefficient of Variance
Cmax
(ng/mL) | tmax
(h) | t1/2
(h) | AUC0-48h
(ng•h/mL) |
|
---|---|---|---|---|
Baseline-corrected estrone (% CV) |
3.74 (29) |
8.00 (27) |
14.26 (26) |
62.03 (34) |
Equilin (% CV) |
3.69 (44) |
8.05 (36) |
11.28 (28) |
58.25 (53) |
Δ8,9 Dehydroestrone (% CV) |
0.74 (32) |
7.55 (37) |
14.14 (26) |
12.93 (39) |
Cmax = peak plasma concentration; tmax = time peak concentration occurs; t1/2 = apparent terminal-phase disposition half-life; AUC0-48h = total area under the concentration-time curve from time zero to time of last quantifiable concentration (48h); CV= Coefficient of Variance
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 portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The mean (SD) apparent terminal elimination half-life (t½) of conjugated estrone is 14 (± 6) hours and conjugated equilin is 11 (± 6) hours.
A randomized, double-blind, placebo-controlled, dose-ranging, multi-center clinical study was conducted to evaluate the safety and effectiveness of ENJUVIA tablets for the treatment of vasomotor symptoms in 281 naturally or surgically postmenopausal women aged 26 to 65 years who were experiencing a minimum of seven moderate to severe hot flushes per day or 50 per week at randomization. The majority (81%) of patients were Caucasian (n=228) and 17.4% were Black (n=49). Women were randomized to receive ENJUVIA tablets 0.3 mg, 0.625 mg, 1.25 mg, or placebo once daily for 12 weeks.
ENJUVIA (0.3 mg, 0.625 mg, and 1.25 mg tablets) was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms (Table 5 and Table 6).
0.3 mg
n=66 | 0.625 mg
n=71 | 1.25 mg
n=69 | Placebo
n=70 |
|
---|---|---|---|---|
Baseline | ||||
Mean (SD) |
104.3 (57.7) |
97.3 (82.1) |
86.8 (42.1) |
96.4 (58.2) |
Week 4 | ||||
Mean (SD) |
47.0 (52.9) |
23.3 (26.9) |
24.6 (47.0) |
57.8 (47.5) |
Mean Change from Baseline (SE) |
-49.8 (5.2) |
-72.8 (5.0) |
-68.3 (5.1) |
-37.2 (5.0) |
p-value versus placebo |
0.005 |
<0.001 |
<0.001 |
--- |
Week 12 | ||||
Mean (SD) |
30.7 (47.7) |
12.2 (18.7) |
12.4 (26.3) |
47.5 (49.8) |
Mean Change from Baseline (SE) |
-66.3 (4.6) |
-84.6 (4.4) |
-82.6 (4.5) |
-48.3 (4.5) |
p-value versus placebo |
<0.001 |
<0.001 |
<0.001 |
--- |
ITT= Intent to treat; LOCF= Last Observation Carried Forward, SD= Standard Deviation; SE= Standard Error
0.3 mg
n=66 | 0.625 mg
n=71 | 1.25 mg
n=69 | Placebo
n=70 |
|
---|---|---|---|---|
Baseline | ||||
Mean (SD) |
2.5 (0.3) |
2.5 (0.3) |
2.5 (0.3) |
2.5 (0.3) |
Week 4 | ||||
Mean (SD) |
2.1 (0.8) |
1.9 (1.0) |
1.5 (1.1) |
2.2 (0.8) |
Mean Change from Baseline (SE) |
-0.5 (0.1) |
-0.6 (0.1) |
-1.0 (0.1) |
-0.3 (0.1) |
p-value versus placebo |
0.036 |
0.002 |
<0.001 |
--- |
Week 12 | ||||
Mean (SD) |
1.5 (1.2) |
1.1 (1.2) |
1.0 (1.1) |
1.9 (1.1) |
Mean Change from Baseline (SE) |
-1.0 (0.1) |
-1.4 (0.1) |
-1.5 (0.1) |
-0.6 (0.1) |
p-value versus placebo |
0.023 |
<0.001 |
<0.001 |
--- |
ITT= Intent to treat; LOCF= Last Observation Carried Forward, SD= Standard Deviation; SE= Standard Error
A randomized, double-blind, placebo-controlled, multi-center clinical study was conducted to evaluate the safety and effectiveness of ENJUVIA 0.3 mg tablets for the treatment of symptoms of vulvar and vaginal atrophy in 248 naturally or surgically postmenopausal women between 32 to 81 years of age (mean 58.6 years) who at baseline had ≤ 5% superficial cells on a vaginal smear, a vaginal pH > 5.0, and who identified their most bothersome moderate-to-severe symptom of vulvar and vaginal atrophy. The majority (82%) of the women were Caucasian (n=203), 11% were Hispanic (n=26), 4% were Black (n=9), and 3% were Asian (n=6). All patients were assessed for improvement in the mean change from baseline to Week 12 for three co-primary efficacy variables: most bothersome symptom of vulvar and vaginal atrophy (defined as the moderate to severe symptom that had been identified by the patient as most bothersome to her at baseline); percentage of vaginal superficial cells and percentage of vaginal parabasal cells; and vaginal pH.
In this study, a statistically significant mean change between baseline and Week 12 for the group treated with ENJUVIA 0.3 mg tablets compared to placebo was observed for the symptoms, vaginal dryness and pain with intercourse. See Table 7. ENJUVIA 0.3 mg tablets increased superficial cells by a mean of 17.1% as compared to 2.0% for placebo (statistically significant). A corresponding statistically significant mean reduction from baseline in parabasal cells (41.7% for ENJUVIA 0.3 mg tablets and 6.8% for placebo) was observed at Week 12. The mean reduction between baseline and Week 12 in the pH was 1.69 in the ENJUVIA 0.3 mg tablets group and 0.45 in the placebo group (statistically significant).
Most Bothersome Symptom at Baseline* | ENJUVIA 0.3 mg | Placebo |
---|---|---|
Vaginal Dryness | ||
n |
56 |
54 |
Baseline Severity |
2.52 |
2.54 |
Mean Severity at Week 12 |
0.80 |
1.81 |
Mean Change in Severity from Baseline (s.d.) |
-1.71 (0.85) |
-0.72 (0.66) |
p-value versus placebo |
<0.001 |
--- |
Pain With Intercourse | ||
n |
35 |
40 |
Baseline Severity |
2.74 |
2.70 |
Mean Severity at Week 12 |
0.94 |
1.95 |
Mean Change in Severity from Baseline (s.d.) |
-1.80 (1.02) |
-0.75 (0.95) |
p-value versus placebo |
<0.001 |
--- |
* Treatment differences assessed by ANCOVA or rank ANCOVA (% cell data) with baseline as covariate for the modified intent-to-treat population, last-observation-carried-forward data set.
The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI, and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.
WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 8.
Event | Relative Risk CE vs. Placebo (95% nCI†) | CE n = 5,310 | Placebo n = 5,429 |
---|---|---|---|
Absolute Risk per 10,000 Women-Years |
|||
|
|||
CHD events‡ |
0.95 (0.78-1.16) |
54 |
57 |
|
0.91 (0.73-1.14) |
40 |
43 |
|
1.01(0.71-1.43) |
16 |
16 |
All strokes‡ |
1.33 (1.05-1.68) |
45 |
33 |
|
1.55 (1.19-2.01) |
38 |
25 |
1.47 (1.06-2.06) |
23 |
15 |
|
Pulmonary embolism‡ |
1.37 (0.90-2.07) |
14 |
10 |
Invasive breast cancer‡ |
0.80 (0.62-1.04) |
28 |
34 |
Colorectal cancer¶ |
1.08 (0.75-1.55) |
17 |
16 |
Hip fracture‡ |
0.65 (0.45-0.94) |
12 |
19 |
0.64 (0.44-0.93) |
11 |
18 |
|
0.58 (0.47-0.72) |
35 |
59 |
|
0.71 (0.64-0.80) |
144 |
197 |
|
1.08 (0.88-1.32) |
53 |
50 |
|
1.04 (0.88-1.22) |
79 |
75 |
|
Global indexÞ |
1.02 (0.91-1.13) |
206 |
201 |
For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the “global index” was a 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 8).
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 examined10 (see Table 8).
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 nonsignificant 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 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 9. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
Event | Relative Risk CE/MPA vs. Placebo (95% nCI‡) | CE/MPA n = 8,506 | Placebo
n = 8,102 |
---|---|---|---|
Absolute Risk per 10,000 Women-Years |
|||
|
|||
CHD events |
1.23 (0.99-1.53) |
41 |
34 |
|
1.28 (1.00-1.63) |
31 |
25 |
|
1.10 (0.70-1.75) |
8 |
8 |
All strokes |
1.31 (1.03-1.68) |
33 |
25 |
|
1.44 (1.09-1.90) |
26 |
18 |
Deep vein thrombosis§ |
1.95 (1.43-2.67) |
26 |
13 |
Pulmonary embolism |
2.13 (1.45-3.11) |
18 |
8 |
Invasive breast cancer¶ |
1.24 (1.01-1.54) |
41 |
33 |
Colorectal cancer |
0.61 (0.42-0.87) |
10 |
16 |
Endometrial cancer§ |
0.81 (0.48-1.36) |
6 |
7 |
Cervical cancer§ |
1.44 (0.47-4.42) |
2 |
1 |
Hip fracture |
0.67 (0.47-0.96) |
11 |
16 |
Vertebral fractures§ |
0.65 (0.46-0.92) |
11 |
17 |
Lower arm/wrist fractures§ |
0.71 (0.59-0.85) |
44 |
62 |
Total fractures§ |
0.76 (0.69-0.83) |
152 |
199 |
Overall Mortality# |
1.00 (0.83-1.19 |
52 |
52 |
Global IndexÞ |
1.13 (1.02-1.25) |
184 |
165 |
Timing of the initiation of estrogen 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]).
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy 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 with 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 woman-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD), and mixed types (having features of both AD and VaD). The most common classification of probable dementia in both 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 [seeWarnings 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 with 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 woman-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 to79 years of age, it is unknown whether these findings apply to younger postmenopausal women [seeWarnings 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 [seeWarnings and Precautions (5.3), and Use in Specific Populations (8.5)].
ENJUVIA (synthetic conjugated estrogens, B) Tablets
Store at 20° to 25°C (68° to 77°F) ; excursions are permitted to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature].
Keep this and all drugs out of the reach of children.
Dispense in a tight container with a child-resistant closure.
Pharmacist: Include one “Patient Information” leaflet with each prescription.
See FDA-approved patient labeling (Patient Information)
Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].
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)].
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:
Teva Women’s Health, Inc.
Subsidiary of Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
ENJUVIA® (en joo vē- ǝ)
(synthetic conjugated estrogens, B) Tablets
Read this Patient Informationbefore you start taking ENJUVIA, and each time you refill your ENJUVIA prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.
What is the most important information I should know about ENJUVUA (an estrogen mixture)?
|
What is ENJUVIA?
ENJUVIA is a prescription medicine that contains a mixture of estrogen hormones.
What is ENJUVIA used for?
ENJUVIA is used after menopause to:
Who should not take ENJUVIA?
Do not take ENJUVIA if you:
What should I tell my healthcare provider before I take ENJUVIA?
Before you take ENJUVIA, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how ENJUVIA works. ENJUVIA 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 a new medicine.
How should I take ENJUVIA?
What are the possible side effects of ENJUVIA?
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:
Call your healthcare provider right away if you get any of the following warning signs, or any other unusual symptoms that concern you:
Less serious, but common side effects include:
These are not all the possible side effects of ENJUVIA. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away.
You may report side effects to Teva Pharmaceuticals at 1-888-483-8279 or to FDA at 1-800-FDA-1088.
What can I do to lower my chances of a serious side effect with ENJUVIA?
How should I store ENJUVIA?
Keep ENJUVIA and all other medicines out of the reach of children.
General information about safe and effective use of ENJUVIA.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take ENJUVIA for conditions for which it was not prescribed. Do not give ENJUVIA to other people, even if they have the same symptoms you have. It may harm them.
This leaflet provides a summary of the most important information about ENJUVIA. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about ENJUVIA that is written for healthcare professionals.
You may also obtain further information by calling the toll free number 1-888-483-8279.
What are the ingredients in ENJUVIA?
Active Ingredient: synthetic conjugated estrogens, B.
Inactive Ingredients: ascorbyl palmitate, butylated hydroxyanisole, colloidal silicon dioxide, edetate disodium dehydrate, plasticized ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, purified water, iron oxide red, titanium dioxide, polyethylene glycol, polysorbate 80, triacetate and triacetin/glycerol. In addition, the
This Patient Information has been approved by the U.S. Food and Drug Administration.
Manufactured By:
Teva Women’s Health, Inc.
Subsidiary of Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
Revised: 06/2015
ENJUVIA
synthetic conjugated estrogens, b tablet, film coated |
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ENJUVIA
synthetic conjugated estrogens, b tablet, film coated |
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ENJUVIA
synthetic conjugated estrogens, b tablet, film coated |
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ENJUVIA
synthetic conjugated estrogens, b tablet, film coated |
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ENJUVIA
synthetic conjugated estrogens, b tablet, film coated |
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Labeler - Teva Women's Health, Inc. (017038951) |