Angeliq drospirenone and estradiol 1 mg; .5 mg Tablet, Film Coated — NDC 50419-483-03 (Billing 50419-0483-03)
This is a package of Angeliq drospirenone and estradiol 1 mg; .5 mg Tablet, Film Coated from Bayer HealthCare Pharmaceuticals Inc., marketed since Nov 2005 and currently FDA-listed; retail pharmacies pay about $6.37 per unit (NADAC). It is the main listing for this product, which comes in 2 package sizes.
NDC database record
One package, one record: these facts belong to NDC 50419-483-03 alone.
- Record
- FDA NDC Directory package listing · Human prescription drug
- Code segments
- 50419 labeler · 483 product · 03 package
- Package marketed since
- Feb 29, 2012
- Sample package
- No — commercial package
- Listing certified through
- Dec 31, 2027
- Barcode (UPC-A, from the NDC)
- 3 5041948303 2
- Medicaid fills, this package
- 235 prescriptions in the last four reported quarters
- FDA record last changed
- Oct 8, 2026
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 059061
- GCN: 24602
- GPI-14 (Medi-Span): 24993002400320
- HICL (First Databank): 039160
- AHFS class code: 68:16.04.00
- RxCUI (RxNorm): 1483549
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 8, 2026
- FDA label on DailyMed · label index refreshed Oct 6, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 8, 2026
RxNorm drug class
This medicine belongs to the Progestin class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Patient education
Supplement & herbal interactions
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 6, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $6.367 | $534.80 / 84 tablets |
| Medicaid paysCMS SDUD · 12 mo | $6.43 | $539.93 / 84 tablets |
| Medicare drug plans payPart D · Q2 2026 | $6.35 | $533.43 / 84 tablets |
Where does this data come from?
- CMS NADAC weekly file · file of Oct 7, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q4 2025
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Marketing end | Status |
|---|---|---|---|---|---|---|
| 50419-0483-03 You're viewing this Main listing | 3 BLISTER PACK in 1 CARTON / 28 TABLET, FILM COATED in 1 BLISTER PACK | $6.37 / ea | $534.80 | 2012-02-29 | — | Active |
| 50419-0483-72 50419-483-72 | 1 BLISTER PACK in 1 CARTON / 14 TABLET, FILM COATED in 1 BLISTER PACK | — | — | 2012-02-29 | — | Active |
In Medicaid, this is the most-dispensed pack of this product — about 100% of fills over the last four reported quarters. See all packs ↓
Pack size FAQ
What quantity is in this package?
What NDC number is used to bill for this package of Angeliq drospirenone and estradiol 1 mg; .5 mg Tablet, Film Coated?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Angeliq 1 mg/1; .5 mgthis 50419-0483-03 | Bayer | 28 tablets | $6.367 | AB | Availability likely | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 8, 2026
- FDA Orange Book · refreshed Oct 3, 2026
- CMS NADAC weekly file · file of Oct 7, 2026
Availability & generic status
The FDA lists approved generic versions of this medicine, but that does not always mean a pharmacy can get one today. Patent rules, launch agreements, supply and pricing can affect when generics actually arrive.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 8906890 ↗ | Drug product | — | Oct 22, 2031 |
Is there a generic version of ANGELIQ 0.5 MG-1 MG TABLET?
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Can a generic come out before the last patent expires?
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Where does this data come from?
- FDA Orange Book · refreshed Oct 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 6, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII 1K09F3G675
Ferric oxide red is an inorganic iron compound used as a colorant in medicines. It gives tablets, capsules, or other dosage forms a red or reddish tint for identification and appearance.
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UNII 3NXW29V3WO
Hypromellose is a plant-based thickener made from cellulose. It's used in medicines as a binder to hold ingredients together, a coating for tablets, and a thickener for liquids.
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UNII EWQ57Q8I5X
Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
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UNII 70097M6I30
Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
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UNII 30IQX730WE
Polyethylene glycol 6000 is a synthetic polymer made from ethylene glycol units. It acts as a binder, filler, and solubilizer in medicines to help hold ingredients together, add bulk, and improve how well active drugs dissolve and absorb.
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UNII K0KQV10C35
Povidone K25 is a synthetic polymer made from vinyl pyrrolidone. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in the stomach for better absorption.
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UNII O8232NY3SJ
A plant-based carbohydrate derived from corn kernels. It acts as a filler to add bulk, a binder to hold ingredients together, and a disintegrant to help the tablet break apart in your stomach for absorption.
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UNII 7SEV7J4R1U
A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
9 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 6, 2026
- FDA openFDA NDC Directory · synced Oct 8, 2026
Inactive ingredient FAQ
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Manufacturer & labeler
More NDCs from Bayer HealthCare Pharmaceuticals Inc. labeler code 50419
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- Lynkuet elinzanetant 60 mg Capsule NDC 50419-475-05
- Angeliq drospirenone and estradiol .5 mg; .25 mg Tablet, Film Coated NDC 50419-482-03
- Nexavar sorafenib 200 mg Tablet, Film Coated NDC 50419-488-58
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- Climara Pro Estradiol and Levonorgestrel .045 mg/d; .015 mg/d Patch NDC 50419-491-04
- Betaseron interferon beta-1b Kit NDC 50419-524-05
- Kerendia finerenone 10 mg Tablet, Film Coated NDC 50419-540-01
- Kerendia finerenone 20 mg Tablet, Film Coated NDC 50419-541-01
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 8, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
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) ]. The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and 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 (5.4) , Use in Specific Populations (8.5) , and Clinical Studies (14.5) ] . Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.4) and Clinical Studies (14.4 , 14.5) ]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the 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… [Excerpted — this section continues on DailyMed.]
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE 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.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Each pack of Angeliq covers 28 days of treatment. Treatment is continuous, which means that the next pack follows immediately without a break. The tablets are to be swallowed whole with some liquid irrespective of food intake and should preferably be taken at the same time every day.
In case a tablet is forgotten, it should be taken as soon as possible. If more than 24 hours have elapsed, the missed tablet should not be taken. If several tablets are forgotten, bleeding may occur.
Women who do not take estrogens or women who change from a continuous combination product may start treatment at any time. Women changing from a continuous sequential or cyclic hormone therapy (HT) should complete the current cycle of therapy before initiating Angeliq therapy. Start therapy with Angeliq 0.25 mg drospirenone (DRSP)/0.5 mg estradiol (E2) once daily for the treatment of moderate to severe vasomotor symptoms due to menopause.
Dosage adjustment should be guided by the clinical response ( 2.1 ) Start therapy with Angeliq 0.5 mg DRSP/1 mg E2 once daily for the treatment of moderate to severe vulvar and vaginal atrophy due to menopause ( 2.2 )
2.1Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause One Angeliq 0.25 mg DRSP/0.5 mg E2 tablet or one Angeliq 0.5 mg DRSP/1 mg E2 tablet taken by mouth once daily.
2.2Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause One Angeliq 0.5 mg DRSP/1 mg E2 tablet taken by mouth once daily. 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.
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Angeliq 0.25 mg DRSP/0.5 mg E2 Tablets: round, biconvex, yellow, film-coated, embossed with a "EL" inside a hexagon Angeliq 0.5 mg DRSP/1 mg E2 Tablets : round, biconvex, pink, film-coated, embossed with a "CK" inside a hexagon Tablet: 0.25 mg DRSP/0.5 mg E2 and 0.5 mg DRSP/1 mg E2 ( 3 )
⛔ Contraindications ▾
4 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) ]. 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) ] Undiagnosed abnormal genital bleeding ( 4 , 5.3 ) Breast cancer or a history of breast cancer ( 4 , 5.3 ) Estrogen-dependent neoplasia ( 4 , 5.3 ) Active DVT, PE, or a history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke and MI), or history of these conditions ( 4 , 5.1 ) Renal impairment ( 4 , 5.2 ) Hepatic impairment or disease ( 4 , 5.2 ) Adrenal insufficiency ( 4 , 5.2 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) Known anaphylactic reaction, angioedema, or hypersensitivity to Angeliq ( 4 , 5.16 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Do not use with conditions that predispose to hyperkalemia (
5.2Estrogens 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 even… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 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 to… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG 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/… [Excerpted — this section continues on DailyMed.]
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS
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… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
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 gest… [Excerpted — this section continues on DailyMed.]
🧒 Pediatric Use ▾
8.4Pediatric Use Angeliq is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
🧓 Geriatric Use ▾
8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Angeliq to determine whether those over 65 years of age differ from younger women in their response to Angeliq. The Women's Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.1 , 5.3) and Clinical Studies (14.4) ] .
In the WHI estrogen-alone substudy (daily CE [0.625 mg] versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions (5.1) and Clinical Studies (14.4) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.4) , and Clinical Studies (14.5) ] .
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions (5.4) , and Clinical Studies (14.5) ] .
🆘 Overdosage ▾
10 OVERDOSAGE Overdosage of estrogen plus progestogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Angeliq therapy with institution of appropriate symptomatic care.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol (E2) is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle.
After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.
To date, two estrogen receptors have been identified. These will vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), through a negative feedback mechanism.
Estrogens act to reduce the elevated concentrations of these gonadotropins seen in postmenopausal women. DRSP is a synthetic progestin and spironolactone analog with antimineralocorticoid activity. In animals and in vitro , drospirenone has antiandrogenic activity, but no glucocorticoid, antiglucocorticoid, estrogenic, or androgenic activity.
Progestins counter estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.
12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to Angeliq nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen plus progestin products to infer efficacy or safety for the individual woman may not be valid.
12.3Pharmacokinetics Absorption Serum concentrations of DRSP reach peak concentrations approximately 1 hour after administration of Angeliq and mean absolute bioavailability of DRSP ranges from 76–85%. Following oral administration, the median T max of serum estradiol was approximately 2 hours after dosing with Angeliq and T max ranged between 0.3-10 hours. The pharmacokinetics of DRSP are dose proportional within the dose range of 0.25–4 mg.
Following daily dosing of Angeliq, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for DRSP and estradiol were 2.3 and 2.0, respectively, following multiple doses of 0.5 mg DRSP/1 mg E2, and 2.6 and 1.6, respectively, following multiple doses of 0.25 mg DRSP/0.5 mg E2. Mean concentrations at 2 hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with Angeliq (0.5 mg DRSP/1 mg E2) for 365 days.
Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and a summary of primary pharmacokinetic parameters following the administration of 0.25 mg DRSP/0.5 mg E2 or 0.5 mg DRSP/1 mg E2 at steady state is presented in Table 3. Figure 1: Mean (± SD) steady state serum drospirenone and estradiol concentrations following daily oral administration of 0.25 or 0.5 mg Drospirenone and 0.5 or 1 mg Estradiol 0.25 mg DRSP/0.5 mg E2 0.5 mg DRSP/1 mg E2 Table 3: Mean (± SD) Steady State Pharmacokinetic Parameters after Administration of Tablets Containing 0.25 or 0.5 mg Drospirenone and 0.5 or 1 mg Estradiol Parameter Unit 0.25 mg DRSP/0.5 mg E2 0.5 mg DRSP/1 mg E2 Drospirenone (DRSP) N=12 N=17 Except for T max , the mean PK results of DRSP, E2, and E1 are displayed as the arithmetic mean and standard deviation (SD, in parentheses).
For T max the median and range are provided. C max =Maximum observed serum concentration T max =time to reach C max AUC (0-24)… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol (E2) is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle.
After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.
To date, two estrogen receptors have been identified. These will vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), through a negative feedback mechanism.
Estrogens act to reduce the elevated concentrations of these gonadotropins seen in postmenopausal women. DRSP is a synthetic progestin and spironolactone analog with antimineralocorticoid activity. In animals and in vitro , drospirenone has antiandrogenic activity, but no glucocorticoid, antiglucocorticoid, estrogenic, or androgenic activity.
Progestins counter estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1How Supplied Angeliq is supplied in packages of three blister packs: Angeliq 0.25 mg DRSP/0.5 mg E2 Angeliq 0.25 mg DRSP/0.5 mg E2 tablets are available as round, biconvex yellow film-coated tablets embossed with "EL" inside a hexagon. 3 blisters of 28 tablets NDC 50419-482-03 Angeliq 0.5 mg DRSP/1 mg E2 Angeliq 0.5 mg DRSP/1 mg E2 tablets are available as round, biconvex pink film-coated tablets embossed with "CK" inside a hexagon. 3 blisters of 28 tablets NDC 50419-483-03
16.2Storage and Handling Store at 20° to 25° C (68° to 77° F); excursions permitted to 15°–30° C (59°–86° F) [see USP Controlled Room Temperature].
📦 Storage and Handling ▾
16.2Storage and Handling Store at 20° to 25° C (68° to 77° F); excursions permitted to 15°–30° C (59°–86° F) [see USP Controlled Room Temperature].
📋 Description ▾
11 DESCRIPTION Angeliq tablets, for oral administration, provide a hormone regimen consisting of drospirenone and estradiol. Drospirenone, (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3´,4´,6, 6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene- 17,2´(5H)-furan]-3,5´(2H)-dione (CAS) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C 24 H 30 O 3 . Estradiol USP, (Estra-1,3,5(10)-triene-3,17-diol,17ß), has a molecular weight of 272.39 and the molecular formula is C 18 H 24 O 2 .
The structural formulas are as follows: The inactive ingredients in Angeliq 0.5 mg DRSP/1 mg E2 tablets are: lactose monohydrate NF, corn starch NF, pregelatinized starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, and red ferric oxide pigment NF. The inactive ingredients in Angeliq 0.25 mg DRSP/0.5 mg E2 tablets are: lactose monohydrate NF, corn starch NF, pregelatinized starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, and yellow ferric oxide pigment NF.
Chemical Structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION 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) ].
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics Absorption Serum concentrations of DRSP reach peak concentrations approximately 1 hour after administration of Angeliq and mean absolute bioavailability of DRSP ranges from 76–85%. Following oral administration, the median T max of serum estradiol was approximately 2 hours after dosing with Angeliq and T max ranged between 0.3-10 hours. The pharmacokinetics of DRSP are dose proportional within the dose range of 0.25–4 mg.
Following daily dosing of Angeliq, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for DRSP and estradiol were 2.3 and 2.0, respectively, following multiple doses of 0.5 mg DRSP/1 mg E2, and 2.6 and 1.6, respectively, following multiple doses of 0.25 mg DRSP/0.5 mg E2. Mean concentrations at 2 hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with Angeliq (0.5 mg DRSP/1 mg E2) for 365 days.
Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and a summary of primary pharmacokinetic parameters following the administration of 0.25 mg DRSP/0.5 mg E2 or 0.5 mg DRSP/1 mg E2 at steady state is presented in Table 3. Figure 1: Mean (± SD) steady state serum drospirenone and estradiol concentrations following daily oral administration of 0.25 or 0.5 mg Drospirenone and 0.5 or 1 mg Estradiol 0.25 mg DRSP/0.5 mg E2 0.5 mg DRSP/1 mg E2 Table 3: Mean (± SD) Steady State Pharmacokinetic Parameters after Administration of Tablets Containing 0.25 or 0.5 mg Drospirenone and 0.5 or 1 mg Estradiol Parameter Unit 0.25 mg DRSP/0.5 mg E2 0.5 mg DRSP/1 mg E2 Drospirenone (DRSP) N=12 N=17 Except for T max , the mean PK results of DRSP, E2, and E1 are displayed as the arithmetic mean and standard deviation (SD, in parentheses).
For T max the median and range are provided. C max =Maximum observed serum concentration T max =time to reach C max AUC (0-24)=area under the serum concentration-time curve from 0 h up to 24 h after daily multiple administration t 1/2 =half-life N/A=Not available C max ng/mL 5.70 (1.42) 8.50 (1.63) T max h 0.992 (0.667 – 1.03) 1.02 (1 – 2.03) AUC (0-24) ng∙h/mL 48.5 (13.7) 84.3 (19.7) t 1/2 h N/A
39.2N=16 (8.5) Estradiol (E2) C max pg/mL 29.7 (6.80) 63.7 (24.2) T max h 2.33 (0.32 – 10) 2.01 (0.5 – 6.02) AUC (0-24) pg∙h/mL 515.4 (142.0) 882 (267) t 1/2 h N/A 20.5 (2.67) Estrone (E1) C max pg/mL 165.7 (40.4) 362 (122) T max h 3.98 (1.98 – 7.05) 6 (3.99 – 10) AUC (0-24) pg∙h/mL 2839 (658) 5561 (1689) t 1/2 h N/A 19.9 (2.10) Effect of Food The effect of food on the absorption and bioavailability of DRSP and E2 have not been investigated following the administration of Angeliq. However, clinical studies with different formulations containing DRSP or E2 have shown that the bioavailability of both drugs is not affected by concomitant food intake.
Distribution The mean volume of distribution of DRSP is
4.2L/kg. DRSP does not bind to SHBG or CBG but binds about 97% to other serum proteins. The distribution of exogenous estrogens is similar to that of endogenous estrogens.
Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1% – 2% is unbound. Metabolism Mean clearance of DRSP is 1.2 mL/min/kg.
DRSP is extensively metabolized after oral administration. The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active.
DRSP is also subject to oxidative metabolism catalyzed by CYP 3A4. Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions.
These transformations take place mainly in the liver. Estradiol is converted revers… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to Angeliq nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen plus progestin products to infer efficacy or safety for the individual woman may not be valid.
🔬 Clinical Studies ▾
14 CLINICAL STUDIES
14.1Effects on Vasomotor Symptoms in Postmenopausal Women Angeliq 0.25 mg DRSP/0.5 mg E2 The efficacy of Angeliq 0.25 mg DRSP/0.5 mg E2 for reducing the frequency and severity of moderate to severe vasomotor symptoms was evaluated in a randomized, double-blind, placebo-controlled trial. A total of 735 postmenopausal women ≥ 40 years of age with a minimum of 7 to 8 moderate to severe hot flashes daily or 50 to 60 moderate to severe hot flashes weekly were randomized to one of the two doses of Angeliq, including DRSP 0.25 mg/0.5 mg E2, estrogen monotherapy, or placebo.
The median age of study participants was 53 years and 68% were Caucasian. Efficacy for vasomotor symptoms was assessed during the 12 weeks of treatment. Compared to placebo, women receiving Angeliq 0.25 mg DRSP/0.5 mg E2 achieved statistically significant reduction in the frequency and severity of moderate to severe vasomotor symptoms at Week 4 and at Week 12.
The mean difference in daily reduction of frequency of hot flushes between Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo were approximately -2 episodes at Week 4 and -3 episodes at Week 12. Table 4 shows the mean number of hot flushes in the Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo groups and the treatment difference between Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo treatment at Week 4 and at Week 12. Table 4: Summary Tabulation of the Number of Hot Flushes Per Day – Mean Values and Comparisons Between the Active Treatment Group and the Placebo Group, Last Observation Carried Forward Treatment No. of Hot Flushes/Day Time Period (week) Baseline Mean Mean Change from Baseline Mean change from baseline, difference from placebo, 95% confidence interval, and p-value based on an ANCOVA model with treatment and pooled center as factors and baseline measurement as covariate Difference from Placebo (95% CI) p-Values vs.
Placebo DRSP/E2 (0.25 mg/0.5 mg) [n=175] Week 4 10.68 -5.46 -2.02 (-2.89, -1.16) <0.0001 Week 12 10.68 -7.71 -3.17 (-3.97, -2.37) <0.0001 Placebo [n=176] Week 4 10.53 -3.44 - - Week 12 10.53 -4.54 - - Angeliq 0.5 mg DRSP/1 mg E2 Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bioequivalence of the E2 component of the Angeliq combination product with a currently marketed 1 mg E2 product. The multiple-dose bioequivalence study evaluated the bioequivalence of E2 from a tablet containing DRSP (2 mg) and E2 (1 mg) relative to E2 1 mg tablet.
Angeliq 0.5 mg DRSP/1 mg E2 tablets met the criteria for bioequivalence to the E2 1 mg comparator.
14.2Effects on Endometrium in Postmenopausal Women Angeliq 0.25 mg DRSP/0.5 mg E2 In a one year clinical trial, 661 postmenopausal women were treated with Angeliq 0.25 mg DRSP/0.5 mg E2 (N=489) or a comparator drug (N=172). Endometrial biopsies were performed on 407 (83.2%) women in the Angeliq group during the treatment period. No endometrial hyperplasias occurred during or after one year of treatment.
See Table 5 . Angeliq 0.5 mg DRSP/1 mg E2 In a one year clinical trial of 1,142 postmenopausal women treated with 1 mg E2 alone or 1 mg E2 + 0.5, 1, 2, or 3 mg DRSP, endometrial biopsies were performed on 966 (84.6%) women during the treatment period. Eight women in the E2 monotherapy group developed endometrial hyperplasia (4 simple hyperplasia with no cytological atypia, 3 complex hyperplasia with no cytological atypia, and 1 complex hyperplasia with cytological atypia), and one woman in the 1 mg E2+2 mg DRSP group developed simple hyperplasia with no cytological atypia.
Table 5 shows that there were no diagnoses of endometrial hyperplasia in the Angeliq group. Table 5: Incidence of Endometrial Hyperplasia after up to 12 Months of Treatment E2 1 mg Angeliq 0.25 mg DRSP/0.5 mg E2 Angeliq 0.5 mg DRSP/1 mg E2 Total No. Subjects Treated 226 489 227 Total No. of On-Treatment Biopsies Includes evaluable and unevaluable endometrial biopsy results 197 (87.2%) 407 (83.2%) 191 (84.1%) Hyperplasia 8 (4%) 0 (0%) 0 (0… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month oral carcinogenicity study in mice dosed with 10 mg/kg/day DRSP alone or 1+0.01, 3+0.03 and 10+0.1 mg/kg/day of DRSP and ethinyl estradiol, 0.24 to 10.3 times the exposure (AUC of drospirenone) of women taking a 1 mg dose, there was an increase in carcinomas of the Harderian gland in the group that received the high dose of drospirenone alone. In a similar study in rats given 10 mg/kg/day drospirenone alone or 0.3+0.003, 3+0.03 and 10+0.1 mg/kg/day drospirenone and ethinyl estradiol, 2.3 to 51.2 times the exposure of women taking a 1 mg dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of drospirenone.
Drospirenone was not mutagenic in a number of in vitro (Ames, Chinese Hamster Lung gene mutation and chromosomal damage in human lymphocytes) and in vivo (mouse micronucleus) genotoxicity tests. Drospirenone increased unscheduled DNA synthesis in rat hepatocytes and formed adducts with rodent liver DNA but not with human liver DNA.
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month oral carcinogenicity study in mice dosed with 10 mg/kg/day DRSP alone or 1+0.01, 3+0.03 and 10+0.1 mg/kg/day of DRSP and ethinyl estradiol, 0.24 to 10.3 times the exposure (AUC of drospirenone) of women taking a 1 mg dose, there was an increase in carcinomas of the Harderian gland in the group that received the high dose of drospirenone alone. In a similar study in rats given 10 mg/kg/day drospirenone alone or 0.3+0.003, 3+0.03 and 10+0.1 mg/kg/day drospirenone and ethinyl estradiol, 2.3 to 51.2 times the exposure of women taking a 1 mg dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of drospirenone.
Drospirenone was not mutagenic in a number of in vitro (Ames, Chinese Hamster Lung gene mutation and chromosomal damage in human lymphocytes) and in vivo (mouse micronucleus) genotoxicity tests. Drospirenone increased unscheduled DNA synthesis in rat hepatocytes and formed adducts with rodent liver DNA but not with human liver DNA.
📚 References ▾
15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA .
2007;297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease.
Arch Int Med . 2006;166:357-365. Cushman M, et al.
Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA . 2004;292:1573-1580 Curb JD, et al.
Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med . 2006;166:772-780.
Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA .
2003;289:3234-3253. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy.
JAMA . 2006;295:1647-1657. Anderson GL, et al.
Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA . 2003;290:1739-1748.
Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA .
2004;291:2947-2958. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial.
J Bone Miner Res . 2006;21:817-828. Hendrix SL, et al.
Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation . 2006;113:2425-2434.
📄 Patient Package Insert ▾
PATIENT INFORMATION Angeliq ® (an"ju – le – k') (drospirenone and estradiol) Tablets Read this Patient Information before you start using Angeliq and read what you get each time you get a refill your Angeliq prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.
What is the most important information I should know about Angeliq (a combination of estrogen and progestogen)? Do not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes, or dementia (declines of brain function). Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.
Using estrogens with progestogen may increase your chance of getting dementia, based on a study of women 65 years of age and older Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). Using estrogen-alone may increase your chances of getting strokes or blood clots Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age and older Only one estrogen with progestogen product and dose have been shown to increase your chances of getting heart attacks, strokes, breast cancer, and dementia.
Only one estrogen-alone product and dose have been shown to increase your chances of getting strokes, blood clots, and dementia. Because other products and doses have not been studied in the same way, it is not known how the use of Angeliq will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Angeliq.
What is Angeliq? Angeliq is a prescription medicine that contains two kinds of hormones, an estrogen and a progestogen. Angeliq 0.25 mg drospirenone (DRSP)/0.5 mg estradiol (E2) and Angeliq 0.5 mg DRSP/1 mg E2 are both used after menopause to reduce moderate to severe hot flashes.
Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the "change of life" or menopause (the end of monthly menstrual periods).
Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause." When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need to use estrogens.
In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Angeliq. Angeliq 0.5 mg drospirenone (DRSP)/1 mg estradiol (E2) is used after menopause to treat menopausal changes in or around the vagina.
You and your healthcare provider should talk regularly about whether you still need treatment with Angeliq to control these problems. If you use Angeliq only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. Who should not use Angeliq?
Do not start using Angeliq if you: have had your uterus (womb) removed (hysterectomy). Angeliq contains a progestogen to decrease the chances of getting cancer of the uterus. If you do not have a uterus, you do not need a progestogen and you should not use Angeliq. have unusual vaginal bleeding.
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Have been diagnosed with a bleeding disorder. cur… [Excerpted — this section continues on DailyMed.]
📄 Recent Major Changes ▾
Boxed Warning 10/2023 Warnings and Precautions ( 5.3 ) 12/2023
📄 Package Label / Principal Display Panel ▾
Angeliq 0.5 mg Trade Carton NDC 50419-483-01 1 Unit Rx Only Angeliq ® Tablets (Drospirenone and Estradiol) 0.5 mg/1 mg — 0.5 mg/1 mg — 28 tablets — oral angeliq serialized carton .5
Angeliq 0.25 mg Trade Carton NDC 50419-482-01 1 Unit Rx Only Angeliq ® Tablets (Drospirenone and Estradiol) 0.25 mg/0.5 mg — 0.25 mg/0.5 mg — 28 tablets — oral .25 mg serialized label