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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ENJUVIA (NDA-021443)
(ESTROGENS, CONJUGATED SYNTHETIC B)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/15/2024 (SUPPL-13)
5 Warnings and Precautions
5.2 Malignant NeoplasmsAdditions and/or revisions underlined:
…
Breast Cancer
…
One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen- alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy.
…
11/30/2020 (SUPPL-11)
Boxed Warning
(Extensive changes; please refer to label)
4 Contraindications
(Additions and/or revisions underlined)
ENJUVIA is contraindicated in women with any of the following conditions:
Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2)].
Breast cancer or a history of breast cancer [see Warnings and Precautions (5.2)].
Estrogen-dependent neoplasia [see Warnings and Precautions (5.2).
Active DVT, PE, or a history of these conditions [see Warnings and Precautions (5.1)].
Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [see Warnings and Precautions (5.1)].
Known anaphylactic reaction or angioedema or hypersensitivity to CENESTIN.
Hepatic impairment or disease.
5 Warnings and Precautions
5.1 Cardiovascular Disorders
(Extensive changes; please refer to label)
5.2 Malignant Neoplasms
(Additions and/or revisions underlined)
Endometrial Cancer
Clinical surveillance of all women taking estrogen-alone or estrogen plus progestin therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. with unknown etiology. 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 WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. 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) compared to placebo [see Clinical Studies (14.3)].
After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. 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 placebo [see Clinical Studies (14.3)]…
Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with 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. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
Ovarian Cancer
The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24) but was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.
5.14 Exacerbation of Endometriosis
(Additions and/or revisions underlined)
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. Consider the addition of a progestin for women known to have residual endometriosis post-hysterectomy.
5.15 Hereditary Angioedema
(Additions and/or revisions underlined)
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy outweigh the risks in such women.
5.16 Exacerbation of Other Conditions
(Additions and/or revisions underlined)
Estrogen therapy, including ENJUVIA, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas.
Consider whether the benefits of estrogen therapy outweigh the risks in such women.
5.5 Hypercalcemia
(Additions and/or revisions underlined)
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including ENJUVIA, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.
5.6 Visual Abnormalities
(Additions and/or revisions underlined)
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue ENJUVIA pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Discontinue estrogens, including ENJUVIA, if examination reveals papilledema or retinal vascular lesions.
5.9 Exacerbation of Hypertriglyceridemia
(Additions and/or revisions underlined)
In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of ENJUVIA if pancreatitis occurs.
5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice
(Additions and/or revisions underlined)
Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue ENJUVIA.
5.11 Exacerbation of Hypothyroidism
(Additions and/or revisions underlined)
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. Monitor thyroid function in these women during treatment with ENJUVIA to maintain their free thyroid hormone levels in an acceptable range.
5.12 Fluid Retention
(Additions and/or revisions underlined)
Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as a cardiac or renal impairment. Discontinue estrogen-alone therapy with evidence of medically concerning fluid retention
5.13 Hypocalcemia
(Additions and/or revisions underlined)
Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy outweigh the risks in such women.
8 Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
ENJUVIA is not indicated for use in pregnancy. There are no data with the use of ENJUVIA in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies or limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestin) 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
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
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 breast-feeding should be considered along with the mother’s clinical need for ENJUVIA and any potential adverse effects on the breast-fed child from ENJUVIA or from the underlying maternal condition.
8.4 Pediatric Use
(Additions and/or revisions underlined)
Risk Summary
ENJUVIA is not indicated in pediatric patients. Clinical studies have not been conducted in the pediatric population.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
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)].
Patient Information
(Extensive changes; please refer to label)
11/30/2020 (SUPPL-12)
Boxed Warning
(Extensive changes; please refer to label)
4 Contraindications
(Additions and/or revisions underlined)
ENJUVIA is contraindicated in women with any of the following conditions:
Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2)].
Breast cancer or a history of breast cancer [see Warnings and Precautions (5.2)].
Estrogen-dependent neoplasia [see Warnings and Precautions (5.2).
Active DVT, PE, or a history of these conditions [see Warnings and Precautions (5.1)].
Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [see Warnings and Precautions (5.1)].
Known anaphylactic reaction or angioedema or hypersensitivity to CENESTIN.
Hepatic impairment or disease.
5 Warnings and Precautions
5.1 Cardiovascular Disorders
(Extensive changes; please refer to label)
5.2 Malignant Neoplasms
(Additions and/or revisions underlined)
Endometrial Cancer
Clinical surveillance of all women taking estrogen-alone or estrogen plus progestin therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. with unknown etiology. 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 WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. 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) compared to placebo [see Clinical Studies (14.3)].
After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. 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 placebo [see Clinical Studies (14.3)]…
Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with 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. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
Ovarian Cancer
The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24) but was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.
5.14 Exacerbation of Endometriosis
(Additions and/or revisions underlined)
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. Consider the addition of a progestin for women known to have residual endometriosis post-hysterectomy.
5.15 Hereditary Angioedema
(Additions and/or revisions underlined)
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy outweigh the risks in such women.
5.16 Exacerbation of Other Conditions
(Additions and/or revisions underlined)
Estrogen therapy, including ENJUVIA, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas.
Consider whether the benefits of estrogen therapy outweigh the risks in such women.
5.5 Hypercalcemia
(Additions and/or revisions underlined)
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including ENJUVIA, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.
5.6 Visual Abnormalities
(Additions and/or revisions underlined)
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue ENJUVIA pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Discontinue estrogens, including ENJUVIA, if examination reveals papilledema or retinal vascular lesions.
5.9 Exacerbation of Hypertriglyceridemia
(Additions and/or revisions underlined)
In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of ENJUVIA if pancreatitis occurs.
5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice
(Additions and/or revisions underlined)
Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue ENJUVIA.
5.11 Exacerbation of Hypothyroidism
(Additions and/or revisions underlined)
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. Monitor thyroid function in these women during treatment with ENJUVIA to maintain their free thyroid hormone levels in an acceptable range.
5.12 Fluid Retention
(Additions and/or revisions underlined)
Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as a cardiac or renal impairment. Discontinue estrogen-alone therapy with evidence of medically concerning fluid retention
5.13 Hypocalcemia
(Additions and/or revisions underlined)
Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy outweigh the risks in such women.
8 Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
ENJUVIA is not indicated for use in pregnancy. There are no data with the use of ENJUVIA in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies or limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestin) 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
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
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 breast-feeding should be considered along with the mother’s clinical need for ENJUVIA and any potential adverse effects on the breast-fed child from ENJUVIA or from the underlying maternal condition.
8.4 Pediatric Use
(Additions and/or revisions underlined)
Risk Summary
ENJUVIA is not indicated in pediatric patients. Clinical studies have not been conducted in the pediatric population.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
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)].
Patient Information
(Extensive changes; please refer to label)
11/01/2017 (SUPPL-10)
5 Warnings and Precautions
5.2 Malignant NeoplasmsOvarian Cancer
Additions and/or revisions underlined:
… A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.