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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.
CENESTIN (NDA-020992)
(ESTROGENS, CONJUGATED SYNTHETIC A)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/12/2026 (SUPPL-43)
Boxed Warning
Additions and/or revisions underlined:
WARNING: ENDOMETRIAL CANCER WITH UNOPPOSED ESTROGEN IN WOMEN WITH A UTERUS
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen-only 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 menopausal women with abnormal genital bleeding of unknown etiology [see Warnings and Precautions (5.2)].
4 Contraindications
Additions and/or revisions underlined:
CENESTIN is contraindicated in women with any of the following conditions:
Abnormal genital bleeding of unknown etiology [see Warnings and Precautions (5.2)].
…
5 Warnings and Precautions
5.1 Cardiovascular DisordersAdditions and/or revisions underlined:
CENESTIN is contraindicated in women with active DVT, PE, stroke, or a history of these conditions [see Contraindications (4)]. Immediately discontinue CENESTIN if a PE, DVT, or stroke, occurs or is suspected.
If feasible, discontinue CENESTIN at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
The safety and efficacy of CENESTIN for the prevention of cardiovascular disorders have not been established.
The Women’s Health Initiative (WHI) estrogen-alone trial reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), and stroke, in postmenopausal women (50 to 79 years of age, average age 63.4 years) during 7.2 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] relative to placebo. Analyses were also conducted in women aged 50-59 years, a group of women more likely to present with new onset of moderate to severe VMS compared to women of other age groups in the trial.
Only daily oral 0.625 mg CE was studied in the WHI estrogen-alone trial. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events to lower CE doses, other routes of administration, or other estrogen 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[see Clinical Studies (14.3)].
Venous Thromboembolism
In women aged 50-59 years, the WHI estrogen-alone trial reported a relative risk for PE of 1.53 (95% confidence interval [CI], 0.63, 3.75) for CE compared to placebo, with an absolute risk difference of 4 per 10,000 women-years (WYs; 10 versus 6). The relative risk for DVT was 1.66 (95% CI 0.75, 3.67) for CE compared to placebo, with a risk difference of 5 per 10,000 WYs (13 versus 8).
In the overall study population of women aged 50-79 years, the WHI estrogen-alone trial reported a relative risk of PE of 1.35 (95% CI 0.89, 2.05) for CE compared to placebo, with a risk difference of 4 per 10,000 WYs (14 versus 10). The relative risk for DVT was 1.48 (95% 1.06, 2.07) for CE compared to placebo, with a risk difference of 7 per 10,000 WYs (23 versus 15) [see Clinical Studies (14.3)].
Stroke
In women aged 50-59 years, the WHI estrogen-alone trial reported a relative risk for stroke of
0.99 (95% 0.53, 1.85) for CE compared to placebo, with a risk difference of -1 per 10,000 WYs
versus 17).
In the overall study population of women aged 50-79 years, the WHI estrogen-alone trial reported a relative risk for stroke of 1.35 (95%, 1.07, 1.70) for CE compared to placebo, with a risk difference of 11 per 10,000 WYs (45 versus 34) [see Clinical Studies (14.3)].
Additions and/or revisions underlined:
Endometrial Cancer
In CENESTIN-treated menopausal women with a uterus with persistent or recurring abnormal genital bleeding of unknown etiology, perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to assess for endometrial cancer.
…
Adding a progestogen to estrogen-alone therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There are, however, possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens [see Warnings and Precautions (5.3)].
Breast Cancer
Surveillance measures for breast cancer, such as breast examinations and mammography, are recommended. The use of estrogen-alone therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.
In the WHI estrogen-alone trial, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer. Among women 50-59 years old, the relative risk was 0.82 (95% CI, 0.50, 1.34) for CE compared to placebo, with a risk difference of 5 per 10,000 WYs (24 versus 29). In the overall study population of women aged 50-79 years (average age 63.4 years), the relative risk was 0.79 (95% CI, 0.61, 1.02), with a risk difference of 7 per 10,000 WYs (28 versus 35). [see Clinical Studies (14.3)]. However, a large meta-analysis including 24 prospective studies of postmenopausal women comparing current use of estrogen-only products with use duration of 5 to 14 years (average of 9 years) versus never use reported a relative risk for breast cancer of 1.33 (95% CI, 1.28 to 1.38).2
Ovarian Cancer
A large meta-analysis including 17 prospective studies of postmenopausal women compared current use of estrogen-only products versus never use and reported a relative risk for ovarian cancer of 1.37 (95% CI, 1.26 to 1.50). The duration of hormone therapy use that was associated with an increased risk of ovarian cancer is unknown.3
Newly added subsection:
If CENESTIN is administered with a progestogen, there are possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens. Refer to prescribing information for progestogens indicated for the prevention of endometrial hyperplasia in non-hysterectomized menopausal women receiving estrogens.
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined:
…
Since the trial was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger menopausal women [Clinical Studies (14.3)]. The safety and efficacy of CENESTIN for the prevention of dementia has not been established.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions and/or revisions underlined:
…
What are the ingredients in CENESTIN?
Active Ingredient: synthetic conjugated estrogens, A
Inactive Ingredients: ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80 (except 0.45 mg tablets), pregelatinized starch, titanium dioxide, triethyl citrate and trometamol.
…
02/15/2024 (SUPPL-41)
5 Warnings and Precautions
WARNINGS
…
2. Malignant Neoplasms
a. Breast Cancer
Additions and/or revisions underlined:
…
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-38)
Boxed Warning
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISODERS, PROBABLE DEMENTIA and BREAST CANCER(Additions and/or revisions underlined)
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. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated…
Cardiovascular Disorders and Probable Dementia
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 (14.3, 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)].
Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of 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 progestins 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
Do not use estrogen plus progestin therapy for the prevention of cardiovascular disease or dementia
4 Contraindications
(Additions and/or revisions underlined)
CENESTIN 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)
(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 CENESTIN.
(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 CENESTIN to maintain their free thyroid hormone levels in an acceptable range.
(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 cardiac or renal impairment. Discontinue estrogen-alone therapy, including CENESTIN, with evidence of medically concerning fluid retention.
(Additions and/or revisions underlined)
Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including CENESTIN, outweigh the risks in such women.
(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.
(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.
(Additions and/or revisions underlined)
Estrogen therapy, including CENESTIN, 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.
(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…
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% of the women…
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 it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.
(Additions and/or revisions underlined)
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including CENESTIN, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.
(Additions and/or revisions underlined)
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue CENESTIN pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Discontinue estrogens, including CENESTIN, if examination reveals papilledema or renal vascular lesions.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
CENESTIN is not indicated for use in pregnancy. There are no data with the use of CENESTIN in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital and nongenital birth defects (including cardiac anomalies or 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 in 2% to 4% and 15% to 20%, respectively.
(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 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 CENESTIN and any potential adverse effects on the breast- fed child from CENESTIN or the underlying maternal condition.
(Additions and/or revisions underlined)
CENESTIN 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)].
(Extensive changes; please refer to label)
11/30/2020 (SUPPL-39)
Boxed Warning
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISODERS, PROBABLE DEMENTIA and BREAST CANCER(Additions and/or revisions underlined)
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. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated…
Cardiovascular Disorders and Probable Dementia
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 (14.3, 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)].
Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of 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 progestins 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
Do not use estrogen plus progestin therapy for the prevention of cardiovascular disease or dementia
4 Contraindications
(Additions and/or revisions underlined)
CENESTIN 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)
(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 CENESTIN.
(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 CENESTIN to maintain their free thyroid hormone levels in an acceptable range.
(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 cardiac or renal impairment. Discontinue estrogen-alone therapy, including CENESTIN, with evidence of medically concerning fluid retention.
(Additions and/or revisions underlined)
Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including CENESTIN, outweigh the risks in such women.
(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.
(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.
(Additions and/or revisions underlined)
Estrogen therapy, including CENESTIN, 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.
(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…
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% of the women…
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 it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.
(Additions and/or revisions underlined)
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including CENESTIN, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.
(Additions and/or revisions underlined)
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue CENESTIN pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Discontinue estrogens, including CENESTIN, if examination reveals papilledema or renal vascular lesions.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
CENESTIN is not indicated for use in pregnancy. There are no data with the use of CENESTIN in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital and nongenital birth defects (including cardiac anomalies or 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 in 2% to 4% and 15% to 20%, respectively.
(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 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 CENESTIN and any potential adverse effects on the breast- fed child from CENESTIN or the underlying maternal condition.
(Additions and/or revisions underlined)
CENESTIN 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)].
(Extensive changes; please refer to label)
11/01/2017 (SUPPL-37)
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.