Drug Safety-related Labeling Changes (SrLC)

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ANGELIQ (NDA-021355)

(DROSPIRENONE; ESTRADIOL)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/15/2024 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Malignant Neoplasms

Additions and/or revisions underlined:

Breast Cancer

…

Consistent with the WHI clinical trial, 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. 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.

10/02/2023 (SUPPL-10)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions underlined)

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable Dementia

The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].

The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 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 (5.4), Use in Specific Populations (8.5), and Clinical Studies (14.5)].

Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.4), Clinical Studies (14.4, 14.5)].

Breast Cancer

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.3), and Clinical Studies (14.4)].

Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestin products is not known.

Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestin therapy, taking into account her individual risk profile.

Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen-Alone Therapy

Endometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.3)].

Cardiovascular Disorders and Probable Dementia

The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].

4 Contraindications

(Additions and/or revisions underlined)

Angeliq is contraindicated in women with any of the following conditions:

• Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.3)].
• Breast cancer or a history of breast cancer [see Warnings and Precautions (5.3)].
• Estrogen-dependent neoplasia [see Warnings and Precautions (5.3)].
• Active DVT, PE or history of these conditions [see Warnings and Precautions (5.1)].
• Active arterial thromboembolic disease (for example, stroke and MI) or history of these conditions [see Warnings and Precautions (5.1)].
• Renal Impairment [see Warnings and Precautions (5.2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
• Hepatic impairment or disease [see Warnings and Precautions (5.10), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
• Adrenal insufficiency [see Warnings and Precautions (5.2)].
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
• Known anaphylactic reaction, angioedema, or hypersensitivity to Angeliq or any of its ingredients [see Adverse Reactions (6.2)]

5 Warnings and Precautions

5.1 Cardiovascular Disorders

(Additions and/or revisions underlined)

Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected.

Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and/or obesity) and/or venous thromboembolism (VTE) [for example, personal history or family history of VTE, obesity, systemic lupus erythematosus].

Stroke

The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke 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 strokes per 10,000 women years, respectively) [see Clinical Studies (14.4)]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen with or without progestogen therapy if a stroke occurs or is suspected.

The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 strokes per 10,000 women-years). The increase in risk was demonstrated in year one and persisted 1[see Clinical Studies (14.4)]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected.

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 women-years).1

Coronary Heart Disease

The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in those 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 (14.4)].

The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo2 [see Clinical Studies (14.4)].

Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) in CHD events in those women receiving daily CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years).1

…

Venous Thromboembolism

The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE (DVT and PE) in women receiving daily 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 persisted3 [see Clinical Studies (14.4)]. Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected.

In the WHI estrogen-alone substudy, the risk of VTE 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 years4 [see Clinical Studies (14.4)]. Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected.

If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

5.3 Malignant Neoplasms

Breast Cancer

(Additions and/or revisions underlined)

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. 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 groups5 [see Clinical Studies (14.4)]

 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 (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]6 compared to placebo [see Clinical Studies (14.4)].

Consistent with the WHI clinical trial, 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…

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-fold 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. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology…

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 ovarian cancer 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.7

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 to 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.

5.4 Probable Dementia

(Additions and/or revisions underlined)

In the WHI Memory Study (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 4 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-years [see Use in Specific Populations (8.5), and Clinical Studies (14.5)]…

5.6 Hypercalcemia

(Additions and/or revisions underlined)

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogen plus progestin, including Angeliq if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium concentration.

5.7 Visual Abnormalities

(Additions and/or revisions underlined)

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue Angeliq pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogen plus progestin, including Angeliq, if examination reveals papilledema or retinal vascular lesions.

5.9 Exacerbation of Hypertriglyceridemia

(Additions and/or revisions underlined)

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinuation Angeliq 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 Angeliq.

The clearance of drospirenone was decreased in patients with moderate hepatic impairment.

5.11 Exacerbation of Hypothyroidism

(Additions and/or revisions underlined)

Estrogen administration leads to increased thyroid-binding globulin (TBG) concentrations. 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 Angeliq to maintain their free thyroid hormone concentrations in an acceptable range.

5.12 Fluid Retention

(Additions and/or revisions underlined)

Estrogens plus progestogens 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 plus progestogen therapy, including Angeliq, 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, including Angeliq, outweigh the risks in such women.

5.14 Hyponatremia

(Additions and/or revisions underlined)

As an aldosterone antagonist, drospirenone may increase the possibility of hyponatremia in high-risk women.

5.15 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.

5.16 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, including Angeliq, outweigh the risks in such women.

5.17 Exacerbation of Other Conditions

(Additions and/or revisions underlined)

Estrogen therapy, including Angeliq, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus otosclerosis, chorea minor and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with such conditions.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

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.

From clinical trials with different dose formulations of Angeliq containing E2 dose ranging from 0.5 mg to 1.0 mg combined with DRSP dose ranging from 0.25 mg to 3 mg:

• The most common adverse reactions were gastrointestinal and abdominal pain, female genital bleeding, breast pain and headache. The frequencies of common adverse reactions, in general, were higher for the Angeliq dose formulation containing E2 1 mg compared to Angeliq containing E2 0.5 mg.
• The most common adverse reactions leading to drug discontinuation in controlled clinical trials were abdominal pain, headache, postmenopausal bleeding, breast tenderness, and weight increased.

Placebo-Controlled Trial:

In a placebo-controlled trial evaluating Angeliq 0.25 mg DRSP/0.5 mg E2, 183 postmenopausal women received at least one dose of DRSP 0.25 mg/0.5 mg E2 and 180 received placebo. Study participants were treated for 3 cycles of 28 days each for a total of 12 weeks of treatment. The median age was 53 years (range: 40-77 years) and over 50% of women had a hysterectomy, 68% were Caucasian and 24% were Black. Table 1 summarizes adverse reactions reported in at least 2% of women receiving Angeliq 0.25 mg DRS/0.5 mg E2 and at a higher incidence than subjects receiving placebo.

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following additional adverse reactions have been reported during post-approval use of Angeliq. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establishing a causal relationship to drug exposure…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise patients to read the FDA-Approved patient labeling (Patient Information).

Abnormal Vaginal Bleeding

Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warning and Precautions (5.3)].

Possible Serious Adverse Reactions with Estrogen Plus Progestogen Therapy

Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestogen therapy including cardiovascular disorders, malignant neoplasms, and probable dementia [see Warning and Precautions (5.1, 5.3, 5.4)].

Possible Common Adverse Reactions with Estrogen Plus Progestogen Therapy

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestogen therapy such as headache, breast pain and tenderness, nausea and vomiting [see Adverse Reactions (6)].

PATIENT INFORMATION Angeliq (an"ju–le–k') (drospirenone and estradiol) Tablets

(Extensive changes; please refer to label for complete information)

10/02/2023 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; please refer to label for complete information)

8.2 Lactation Risk Summary

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Estrogens plus progestogens 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. After administration of an oral contraceptive containing DRSP about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 mcg DRSP in an infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Angeliq and any potential adverse effects on the breastfed infant from Angeliq or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

Angeliq is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

11/01/2017 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Malignant Neoplasms

Ovarian 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 to 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.