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Estrogen

Angeliq

Approved 28 Sept 2005OralTablet

The FDA lists this product in 2 strengths and forms.

Indications

Use estrogen, alone or in combination with a progestogen, at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. Angeliq is a combination of an estrogen and progestin indicated in a woman with a uterus for the treatment of: Moderate to severe vasomotor symptoms due to menopause.

( 1.1 ) Moderate to severe vulvar and vaginal atrophy symptoms due to menopause. ( 1.2 ) Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, first consider the use of topical vaginal products.

1.1Treatment of Moderate to Severe Vasomotor

Symptoms due to Menopause Angeliq 0.25 mg drospirenone (DRSP)/0.5 mg estradiol (E2) is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause in a woman with a uterus. Angeliq 0.5 mg DRSP/1 mg E2 is indicated for the treatment of moderate to severe vasomotor symptoms associated due to menopause in a woman with a uterus.

1.2Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal

Atrophy due to Menopause Angeliq 0.5 mg DRSP/1 mg E2 is indicated for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause in a woman with a uterus.

Contraindications

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) ].

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Warnings and precautions

Do not use with conditions that predispose to hyperkalemia (

5.2 Estrogens increase the risk of gallbladder disease ( 5.5 ) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.6 , 5.7 , 5.9 , 5.10 ) Monitor thyroid function in women on thyroid hormone replacement therapy ( 5.11 , 5.19 )

5.1Cardiovascular Disorders

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 placebo 2 [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 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 CHD. 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 plus MPA group and the placebo group in HERS, HERS II, and overall. 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 persisted 3 [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 years 4 [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.

5.2Hyperkalemia

Angeliq contains the progestin DRSP that has antialdosterone activity, including the potential for hyperkalemia in high-risk patients. Angeliq is contraindicated in patients with conditions that predispose to hyperkalemia (renal impairment, hepatic impairment, and adrenal insufficiency). Use caution when prescribing Angeliq to women who regularly take other medications that can increase potassium, such as non-steroidal anti-inflammatory drugs (NSAIDs), potassium-sparing diuretics, potassium supplements, angiotensin converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, heparin and aldosterone antagonists.

Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (for example, ketoconazole, itraconazole, voriconazole), human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors (for example, indinavir, boceprevir), and clarithromycin [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].

5.3 Malignant Neoplasms Breast Cancer 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 groups 5 [see Clinical Studies (14.4) ] The WHI substudy of daily CE (0.625 mg)-alone provided inform

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Interactions

Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7.1 ) Serum potassium concentration may increase in women taking drospirenone with other drugs that have the potential to increase potassium. ( 7.1 )

7.1Metabolic Interactions Effect of Drospirenone on Other Drugs

The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. No significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo . Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4, respectively, were performed and the results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations.

Co-administration of DRSP and drugs that may increase serum potassium: There is a potential for an increase in serum potassium in women taking DRSP with other drugs that may affect electrolytes, such as ACE inhibitors, angiotensin receptor blockers, or NSAIDs, more pronounced in diabetic women [see Warnings and Precautions (5.2) , and Clinical Pharmacology (12.3) ] . Electrolytes were studied in postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker.

After 28 days of exposure to 1 mg E2 and 3 mg DRSP (n=112) or placebo (n=118). The mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium concentrations ≥5.5 mEq/L had cardiovascular adverse events. A drug-drug interaction study of DRSP 3 mg/E2 1 mg versus placebo was performed in mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily.

Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. On Day 14, the ratios for serum potassium C max and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively.

No woman in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L). Of note, occasional or chronic use of NSAID medication was not restricted in any of the Angeliq clinical trials. Effect of Other Drugs on Estrogens and Progestins In vitro and in vivo studies have shown that estrogens and progestins are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.

In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/E2 1.5 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of exposure and a mild increase of peak concentration for DRSP. The E2 exposure and peak concentration were unaffected by ketoconazole, although the exposure and peak concentration of estrone (E1) increased.

Although no clinically relevant effects on any safety or laboratory parameters including serum potassium were observed, this study only assessed women for 10 days. The clinical impact for a woman taking a DRSP-containing combination hormone and chronic use of a CYP3A4/5 inhibitor is unknown. Substances decreasing the exposure and possibly diminishing the efficacy of estrogens and progestins (enzyme inducers) Inducers of CYP3A4 such as St.

John's wort ( Hypericum perforatum ), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens and progestins, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Substances increasing the exposure of estrogens and progestins (enzyme inhibitors) Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit juice did increase the plasma concentrations of the estrogen or the progestin or both [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ].

HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

7.2Interaction with Alcohol

Acute alcohol ingestion during use of hormone therapy may lead to elevations of circulating E2 concentrations.

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Angeliq is not indicated for use in pregnancy . There are no data with the use of Angeliq 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 (estrogens and progestins) before conception or during early pregnancy. In reproduction studies in rats, rabbits and monkeys with oral administration of DRSP either as single compound or in combination with EE, no non-genital teratogenicity was observed.

Adverse developmental outcomes like an increase in fetal mortality and a retardation of fetal maturation were seen in rats and rabbits at exposures to DRSP exceeding the human exposure by a factor of >15 (in rats) or >60 (rabbits). Related to the antiandrogenic activity of drospirenone, a feminization of male fetuses and an impairment of male fertility was observed in rats (>150 times the human exposure to drospirenone) but not in monkeys (at up to more than 300 times the human exposure to drospirenone).

Due to the large safety margins observed in the animal studies only a low likelihood of an increased risk for human pregnancy was concluded ( see Data ). 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. Data Animal Data In an embryo-fetal toxicity study in pregnant rats, DRSP was given from day 6 to 15 of gestation orally at doses of 5, 15 and 45 mg/kg/day, more than 60 times the human exposure starting from the low dose based on AUC of DRSP.

A slight increase in postimplantational loss and a slight increase in retardation of fetal development (e.g. delayed ossification of bones of the feet) was seen in the two higher doses. No teratogenicity was observed in rats. In an embryo-fetal study in rabbits, DRSP was given from day 6 to 18 of gestation orally at doses of 10, 30 and 100 mg/kg/day, about 20, 60 and 250 times the human exposure based on AUC. This resulted in a retardation of fetal development (delayed ossification of small bones, multiple fusions of ribs) at the high dose only and in an increase in fetal loss from the mid dose level.

No compound-related teratogenicity was seen in rabbits. In a further embryo-fetal toxicity study in pregnant rats, DRSP was orally administered in combination with ethinyl estradiol (100:1) from day 6 to 17 of gestation at doses of 1, 3 and 10 mg/kg/day DRSP, at about 1, 3 and 23 times the human exposure to DRSP on basis of AUC. Maternal toxicity (decreased body weight gain and food consumption) was seen starting at the low dose and an increase of early resorptions at the high dose level.

Skeletal variations and retardations were seen in fetuses at the high dose. No malformed fetuses and no effect on the external genitalia of the fetuses were observed. DRSP was administered with ethinyl estradiol (100:1) orally to pregnant rats during late pregnancy from day 14 to 21 of gestation (the period of genital development) at doses of 5, 15 and 45 mg/kg of DRSP, more than 60 times the human exposure starting from the low dose based on AUC of DRSP.

Maternal toxicity (decreased body weight gain) and fetal retardation (decreased fetal body weights) were seen starting at the low dose. There was a dose dependent increase in feminization of male rat fetuses starting at the mid dose level (that is, >150 times the human exposure to DRSP). DRSP was administered with ethinyl estradiol (100:1) orally to pregnant cynomolgus monkeys at doses up to 10 mg/kg DRSP, more than 300 times the human exposure based on AUC from day 20 to 90 of gestation.

A dose-dependent increase of abortions was observed. No teratogenic or feminization effects were seen in any dose group. DRSP was administered with ethinyl estradiol (100:1) in a peri-postnatal study in rats from day 6 to 16 of gestation and day 1 to 22 postpartum at doses of 5, 15 and 45 mg/kg; more than 60 times the human exposure starting from the low dose based on AUC of DRSP. There was a dose dependent delay in fetal development and an increase in mortality of the F1-generation during the lactational phase.

Fertility was impaired in the male offspring at the high dose level.

Adverse reactions

The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.3) ] The most common adverse reactions with Angeliq that occurred in at least 1% of users in clinical trials are: gastrointestinal and abdominal pain, female genital tract bleeding, breast pain and discomfort, and headache.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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. Table 1: Adverse Reactions that Occurred at a Frequency of ≥ 2% with Angeliq 0.25 mg DRSP/0.5 mg E2 and at a Higher Incidence than Placebo Adverse Reaction Angeliq (0.25 mg DRSP/0.5 mg E2) N=183 (100%) n (%) Placebo N=180 (100%) n (%) Gastrointestinal and abdominal pains Gastrointestinal and abdominal pain includes: abdominal pain (overall, lower, and upper), abdominal discomfort, abdominal tenderness 11 (6.0) 5 (2.8) Headache 11 (6.0) 9 (5.0) Vulvovaginal fungal infections 10 (5.5) 1 (0.6) Breast pain Breast pain includes: breast pain, breast tenderness, nipple pain 6 (3.3) 1 (0.6) Nausea 6 (3.3) 2 (1.1) Diarrhea 4 (2.2) 1 (0.6) Peripheral Edema 4 (2.2) 2 (1.1) Pooled data of clinical trials with different dose formulations of Angeliq: Data from 13 clinical trials in postmenopausal women treated with different dose formulations of Angeliq containing 1 mg E2 (1 mg E2 + 0.5 mg – 3.0 mg DRSP; N=2842) were pooled to provide an overall estimate of adverse reactions.

Similarly, data from 2 clinical trials with Angeliq containing 0.5 mg E2 (0.5 mg E2 + DRSP 0.25 mg – 0.5 mg; N=853) were pooled for the same purpose. Table 2 shows adverse reactions reported in at least 1% of women treated with Angeliq. Table 2: Adverse Reactions that Occurred at a Frequency of ≥ 1% in Clinical Trials Adverse Reaction Angeliq containing 1 mg E2 N = 2842 n (%) Angeliq containing 0.5 mg E2 N=853 n (%) Breast pain or discomfort 508 (17.9) 53 (6.2) Female genital tract bleeding 397 (14.0) 21 (2.5) Gastrointestinal and abdominal pain 186 (6.5) 31 (3.6) Cervical polyp 34 (1.2) 3 (0.4) Emotional lability 35 (1.2) 11 (1.3) Migraine 28 (1.0) 5 (0.6) Adverse Reactions in clinical studies were coded using the MedDRA dictionary (version 13.0).

Different MedDRA terms representing the same medical phenomenon have been grouped together as single adverse reactions to avoid diluting or obscuring the true effect.

6.2Postmarketing Experience

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. Immune System Disorders : Hypersensitivity reactions, including rash, pruritis, and urticaria Reproductive system and breast disorders : Breast cancer Vascular disorders : venous and arterial thromboembolic events (peripheral deep venous occlusion, thrombosis and embolism/pulmonary vascular occlusion, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and stroke not specified as hemorrhagic)