Home › NDC Lookup › 69238-1252-08
⚪image loading
(from DailyMed)

Lopreeza estradiol/norethindrone acetate .5 mg; .1 mg Tablet, Film Coated — NDC 69238-1252-8 (Billing 69238-1252-08)

by Amneal Pharmaceuticals NY LLC · 5 CARTON in 1 CELLO PACK / 1 DIALPACK in 1 CARTON / 28 TABLET, FILM COATED in 1 DIALPACK

This is a package of Lopreeza estradiol/norethindrone acetate .5 mg; .1 mg Tablet, Film Coated from Amneal Pharmaceuticals NY LLC, marketed since Oct 2014 and currently FDA-listed. It is this product's only package size.

NDC 69238-1252-08
🏷️ FDA NDC (as labeled) 69238-1252-8 billing pads the package segment with a zero
Rx only Brand On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Oct 1, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

NDC database record

One package, one record: these facts belong to NDC 69238-1252-8 alone.

Record
FDA NDC Directory package listing · Human prescription drug
Code segments
69238 labeler · 1252 product · 8 package
Package marketed since
Oct 1, 2014
Sample package
No — commercial package
Listing certified through
Dec 31, 2026
Barcode (UPC)
0369238125269, 0369238125160
FDA record last changed
Oct 1, 2026

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 69238-1252-8
Product NDC 69238-1252
11-digit billing NDC 69238125208
NCPDP billing unit EA — each (per item)
RxCUI 1359123, 1359124, 1359126, 1359127, 1550964, 1550965
UNII 9S44LIC7OJ, 4TI98Z838E
UPC 0369238125269, 0369238125160
Application # NDA020907
SPL Set ID bf0e39cb-95e7-4831-92d2-0b3f071aeaae
Established class (EPC) Estrogen
Mechanism of action Estrogen Receptor Agonists
Chemical class Estradiol Congeners
DEA schedule Non-controlled
Marketing category NDA AUTHORIZED GENERIC
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2014-10-01
Route ORAL
Dosage form TABLET, FILM COATED
Substance ESTRADIOL; NORETHINDRONE ACETATE
TE code (Orange Book) AB · RLD · RS

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 24993002120305
GPI class Lopreeza
GCN Seq No 062587
GCN 98362
HICL code 007310
Ingredient (HICL) Estradiol/Norethindrone Acet
HIC1 code G
Therapeutic class — broad (HIC1) Female Genital System
HIC2 code G1
Therapeutic class — intermediate (HIC2) Estrogens
HIC3 code G1A
Therapeutic class — specific (HIC3) Estrogenic Agents
AHFS code 68:16.04.00
AHFS class Estrogens
FDB label name LOPREEZA 0.5 MG-0.1 MG TABLET
FDB brand name Lopreeza
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 062587
  • GCN: 98362
  • GPI-14 (Medi-Span): 24993002120305
  • HICL (First Databank): 007310
  • AHFS class code: 68:16.04.00
  • RxCUI (RxNorm): 1359123
Why two NDCs? The FDA registers this code as 69238-1252-8 — a 5-4-1 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the package segment → 69238-1252-08. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Radioactive Diagnostic Agent class.

Pharmacologic class Radioactive Diagnostic Agent, Estrogen
Drug family (ATC) Natural and semisynthetic estrogens, plain, Progestogens and estrogens, sequential preparations
How it works Positron Emitting Activity, Estrogen Receptor Agonists
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name LOPREEZA 0.5 MG-0.1 MG TABLET Ingredient Estradiol/Norethindrone Acet
📗 Our plain-language guide HelloPharmacist
  • Great question. The estradiol (the estrogen part) is what actually relieves your hot flashes, night sweats, and vaginal dryness by replacing the estrogen your body stopped making a...
  • What exactly is this medicine doing for me — why do I need both an estrogen and a progestin?
  • Most women notice things like breast tenderness, some spotting or light bleeding, headaches, or nausea — especially in the first few months. Those are common and usually settle dow...
  • What are the most important side effects I should actually watch out for?
📖 Read our full Estradiol / Norethindrone guide →

Supplement & herbal interactions

🌿 Drug–supplement interaction checker →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

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 systemPer eachPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · quarterly No Part D plan price is available for this NDC in our data.
ℹ️
No price is published for this exact package yet. CMS surveys NADAC per package size, so a different pack of the same drug often has one.
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
69238-1252-08 You're viewing this Main listing 5 CARTON in 1 CELLO PACK / 1 DIALPACK in 1 CARTON / 28 TABLET, FILM COATED in 1 DIALPACK 2014-10-01 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Lopreeza .5 mg/1; .1 mgthis 69238-1252-08 Amneal 28 tablets — AB FDA listed —
Activella .5 mg/1; .1 mg 60846-0231-01 Amneal 28 tablets — AB FDA listed —
Lopreeza .5 mg/1; .1 mg 69238-1609-06 Amneal 28 tablets — AB FDA listed —
About this product: this is an authorized generic — the brand-name product marketed without its brand name. Other versions are listed above, least expensive first.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2014
On the market since
Oct 2014
📍
2026
Currently FDA-listed
12 years listed
🔒
·
Generic approved (availability unconfirmed)
see note
🔒Generic approved by FDA, but pharmacy availability is not confirmed

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.

Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

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.

Loading inactive ingredients from the official FDA label in the background. No external source is being called by this page request.
Where does this data come from?
Source: official FDA Structured Product Labeling (SPL) via DailyMed and the openFDA label index. Structured IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerAmneal Pharmaceuticals NY LLC
Application holderAMNEAL PHARMACEUTICALS LLC
FDA applicationNDA020907 (NDA AUTHORIZED GENERIC)
Labeler code69238
First marketedOct 2014
Product typeHuman Prescription Drug
Portfolio372 products on file

More NDCs from Amneal Pharmaceuticals NY LLC labeler code 69238

The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients 🍼 Nursing Mothers 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📚 References 📄 Patient Package Insert 📄 Recent Major Changes 📄 Package Label / Principal Display Panel
🚨 Boxed Warning ~3 min read ▾

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3 ) , and Clinical Studies (14.5, 14.6) ] . The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (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 the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or 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 (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5) ] .

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed 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 progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3) , and Clinical Studies (14.5, 14.6) ] .

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 the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.6) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment.

See full prescribing information for complete boxed warning Estrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myo… [Excerpted — this section continues on DailyMed.]

🎯 Indications and Usage 171 words ▾

1 INDICATIONS AND USAGE Lopreeza is an estrogen and progestin combination indicated in a woman with a uterus for: Lopreeza 1 mg/0.5 mg and 0.5 mg/0.1 mg are indicated in a woman with a uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1) Prevention of Postmenopausal Osteoporosis (1.3) Lopreeza 1 mg/0.5 mg is also indicated in a woman with a uterus for: Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause (1.2)

1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

1.2Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.

1.3Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

⏱️ Dosage and Administration 180 words ▾

2 DOSAGE AND ADMINISTRATION Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. One tablet to be taken once daily (2)

2.1Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Lopreeza therapy consists of a single tablet to be taken once daily for the treatment of moderate to severe vasomotor symptoms due to menopause. Lopreeza 1 mg/0.5 mg Lopreeza 0.5 mg/0.1 mg

2.2Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Lopreeza therapy consists of a single tablet to be taken once daily for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. Lopreeza 1 mg/0.5 mg

2.3Prevention of Postmenopausal Osteoporosis Lopreeza therapy consists of a single tablet to be taken once daily for the prevention of postmenopausal osteoporosis. Lopreeza 1 mg/0.5 mg Lopreeza 0.5 mg/0.1 mg

💊 Dosage Forms and Strengths 108 words ▾

3 DOSAGE FORMS AND STRENGTHS Lopreeza tablets are available in two strengths: Each tablet of Lopreeza 1 mg/ 0.5 mg contains 1 mg of estradiol and 0.5 mg of norethindrone acetate.The tablets are white, round, bi-convex, film-coated tablets engraved with NOVO 288 on one side and the APIS bull on the other. Each tablet of Lopreeza 0.5 mg/ 0.1 mg contains 0.5 mg of estradiol and 0.1 mg of norethindrone acetate.The tablets are white, round, bi-convex, film-coated tablets engraved with NOVO 291 on one side and the APIS bull on the other.

Lopreeza (estradiol/norethindrone acetate) 1 mg/0.5 mg tablet (3) Lopreeza (estradiol/norethindrone acetate) 0.5 mg/0.1 mg tablet (3)

⛔ Contraindications 169 words ▾

4 CONTRAINDICATIONS Lopreeza is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding Known, suspected, or history of breast cancer Known, past or suspected estrogen-dependent neoplasia Active DVT, PE, or history of these conditions Active arterial thromboembolic disease (for example stroke and MI), or a history of these conditions Known anaphylactic reaction or angioedema or hypersensitivity to Lopreeza Known liver impairment or disease Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known or suspected pregnancy Undiagnosed abnormal genital bleeding (4) Known, suspected, or history of breast cancer (4, 5.2) Known or suspected estrogen-dependent neoplasia (4, 5.2) Active DVT, PE, or history of these conditions (4, 5.1) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions (4, 5.1) Known anaphylactic reaction or angioedema or hypersensitivity to Lopreeza (4) Known liver impairment or disease (4, 5.10) Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4) Known or suspected pregnancy (4, 8.1)

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gall bladder disease (5.4) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10) Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.18)

5.1Cardiovascular Disorders An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported 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 per 10,000 women-years) [see Clinical Studies (14.5) ] .

The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported 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 per 10,000 women-years).

The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.5) ] . Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately. 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 In the WHI estrogen plus progestin substudy, there was a statistically non-significant increase risk of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) reported in 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 (14.5) ] .

In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.5) ]. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (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 pl… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~3 min read ▾

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, (5.2) ] Most common adverse reactions (incidence ≥ 5 percent) are back pain, headache, pain in the extremity, nausea, diarrhea, gastroenteritis, insomnia, emotional lability, upper respiratory tract infection, sinusitis, nasopharyngitis, weight increase, breast pain, post-menopausal bleeding, uterine fibroid vaginal hemorrhage, ovarian cyst, endometrial thickening, viral infection, moniliasis genital, and accidental injury.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-888-824-4336 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. Adverse reactions reported with Lopreeza 1 mg/0.5 mg by investigators in the Phase 3 studies regardless of causality assessment are shown in Table 1. TABLE 1 ALL TREATMENT-EMERGENT ADVERSE REACTIONS REGARDLESS OF RELATIONSHIP REPORTED AT A FREQUENCY OF ≥ 5 PERCENT WITH LOPREEZA 1 MG/0.5 MG Endometrial Hyperplasia Study (12-Months) Vasomotor Symptoms Study (3-Months) Osteoporosis Study (2-Years) Lopreeza 1 mg/0.5 mg 1 mg E 2 Lopreeza 1 mg/0.5 mg Placebo Lopreeza 1 mg/0.5 mg Placebo (n=295) (n=296) (n=29) (n=34) (n=47) (n=48) Body as a Whole Back Pain 6% 5% 3% 3% 6% 4% Headache 16% 16% 17% 18% 11% 6% Digestive System Nausea 3% 5% 10% 0% 11% 0% Gastroenteritis 2% 2% 0% 0% 6% 4% Nervous System Insomnia 6% 4% 3% 3% 0% 8% Emotional Lability 1% 1% 0% 0% 6% 0% Respiratory System Upper Respiratory Tract Infection 18% 15% 10% 6% 15% 19% Sinusitis 7% 11% 7% 0% 15% 10% Metabolic and Nutritional Weight Increase 0% 0% 0% 0% 9% 6% Urogenital System Breast Pain 24% 10% 21% 0% 17% 8% Post-Menopausal Bleeding 5% 15% 10% 3% 11% 0% Uterine Fibroid 5% 4% 0% 0% 4% 8% Ovarian Cyst 3% 2% 7% 0% 0% 8% Resistance Mechanism Infection Viral 4% 6% 0% 3% 6% 6% Moniliasis Genital 4% 7% 0% 0% 6% 0% Secondary Terms Injury Accidental 4% 3% 3% 0% 17%* 4%* Other Events 2% 3% 3% 0% 6% 4% * including one upper extremity fracture in each group Adverse reactions reported with Lopreeza 0.5 mg/0.1 mg by investigators during the Phase 3 study regardless of causality assessment are shown in Table 2.

TABLE 2 ALL TREATMENT-EMERGENT ADVERSE REACTIONS REGARDLESS OF RELATIONSHIP REPORTED AT A FREQUENCY OF ≥ 5 PERCENT WITH LOPREEZA

0.5MG/0.1 MG Lopreeza 0.5 mg/0.1 mg Placebo (n=194) (n=200) Body as a Whole Back Pain 10% 4% Headache 22% 19% Pain in extremity 5% 4% Digestive System Nausea 5% 4% Diarrhea 6% 6% Respiratory System Nasopharyngitis 21% 18% Urogenital System Endometrial thickening 10% 4% Vaginal hemorrhage 26% 12% 6 . 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Lopreeza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary System Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; pre-menstrual-like syndrome; cystitis-like syndrome; ovarian cancer; endometrial hyperplasia; endometrial cancer. Breast Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.

Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction, stroke; increase… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions 174 words ▾

7 DRUG INTERACTIONS Coadministration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone acetate. Similarly, no relevant interaction of norethindrone acetate on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1)

7.1Metabolic Interactions Estradiol In-vitro and in-vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St.

John’s wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and result in side effects. Norethindrone Acetate Drugs or herbal products that induce or inhibit cytochrome P-450 enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone.

👥 Use in Specific Populations ~2 min read ▾

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3) Geriatric Use: An increase risk of probable dementia in women over 65 years of age was reported in the Women’s Health Initiative Memory ancillary studies of the Women’s Health Initiative (5.3, 8.5)

8.1Pregnancy Lopreeza should not be used during pregnancy [see Contraindications (4) ]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

8.3Nursing Mothers Lopreeza should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when Lopreeza is administered to a nursing woman.

8.4Pediatric Use Lopreeza is not indicated in children. Clinical studies have not been conducted in the pediatric population.

8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Lopreeza to determine whether those over 65 years of age differ from younger subjects in their response to Lopreeza. 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 Clinical Studies (14.5) ] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.5) ] .

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. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ] . 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 (5.3) , and Clinical Studies (14.6) ] .

8.6Renal Impairment The effect of renal impairment on the pharmacokinetics of Lopreeza has not been studied.

8.7Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Lopreeza has not been studied.

🤰 Pregnancy 44 words ▾

8.1Pregnancy Lopreeza should not be used during pregnancy [see Contraindications (4) ]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

🧒 Pediatric Use 19 words ▾

8.4Pediatric Use Lopreeza is not indicated in children. Clinical studies have not been conducted in the pediatric population.

🧓 Geriatric Use 220 words ▾

8.5Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Lopreeza to determine whether those over 65 years of age differ from younger subjects in their response to Lopreeza. 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 Clinical Studies (14.5) ] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.5) ] .

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. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ] . 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 (5.3) , and Clinical Studies (14.6) ] .

🆘 Overdosage 40 words ▾

10 OVERDOSAGE Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Lopreeza therapy with institution of appropriate symptomatic care.

🧬 Clinical Pharmacology ~3 min read ▾

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 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 vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH through a negative feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes.

Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

12.2Pharmacodynamics There are no pharmacodynamic data known for Lopreeza tablets.

12.3Pharmacokinetics Absorption Estradiol Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Lopreeza tablets, peak plasma estradiol concentrations are reached within 5 to 8 hours. The oral bioavailability of estradiol following administration of Lopreeza 1 mg/0.5 mg when compared to a combination oral solution is 53%.

Administration of Lopreeza 1 mg/0.5 mg with food did not modify the bioavailability of estradiol. Norethindrone Acetate After oral administration, norethindrone acetate is absorbed and transformed to norethindrone. Norethindrone reaches a peak plasma concentration within 0.5 to 1.5 hours after the administration of Lopreeza tablets.

The oral bioavailability of norethindrone following administration of Lopreeza 1 mg/0.5 mg when compared to a combination oral solution is 100%. Administration of Lopreeza 1 mg/0.5 mg with food increases norethindrone AUC 0-72 by 19% and decreases C max by 36%. The pharmacokinetic parameters of estradiol (E 2 ), estrone (E 1 ), and norethindrone (NET) following oral administration of 1 Lopreeza 1 mg/0.5 mg or 2 Lopreeza 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 3.

TABLE 3 PHARMACOKINETIC PARAMETERS AFTER ADMINISTRATION OF 1 TABLET OF LOPREEZA 1 MG/0.5 MG OR 2 TABLETS OF LOPREEZA

0.5MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMEN 1 x Lopreeza 1 mg/0.5 mg (n=24) 2 x Lopreeza 0.5 mg/0.1 mg (n=24) Mean a (%CV) b Mean a (%CV) b Estradiol c (E 2 ) AUC 0-t (pg/mL*h) 766.5 (48) 697.3 (53) C max (pg/mL) 26.8 (36) 26.5 (37) t max (h): median (range) 6.0 (0.5-16.0) 6.5 (0.5-16.0) t 1/2 (h) d 14.0 e (29) 14.5 f (27) Estrone c (E 1 ) AUC 0-t (pg/mL*h) 4469.1 (48) 4506.4 (44) C max (pg/mL) 195.5 (37) 199.5 (30) t max (h): median (range) 6.0 (1.0-9.0) 6.0 (2.0-9.0) t 1/2 (h) d 10.7 (44) g 11.8 (25) g Norethindrone (NET) AUC 0-t (pg/mL*h) 21043 (41) 8407.2 (43) C max (pg/mL) 5249.5 (47) 2375.4 (41) t max (h) : median (range) 0.7 (0.7-1.25) 0.8 (0.7-1.3)… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action ~1 min read ▾

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 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 vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH through a negative feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes.

Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

📦 How Supplied / Storage and Handling 127 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1How Supplied Lopreeza 1 mg/0.5 mg is a white, film-coated tablet, engraved with NOVO 288 on one side and the APIS bull on the other. It is round, 6mm in diameter and bi-convex. (NDC 69238-1251-6).

It is supplied as 28 tablets in a calendar dial pack dispenser. Lopreeza 0.5 mg/0.1 mg is a white, film-coated tablet, engraved with NOVO 291 on one side and the APIS bull on the other. It is round, 6mm in diameter and bi-convex.

(NDC 69238-1252-6). It is supplied as 28 tablets in a calendar dial pack dispenser.

16.2Storage and Handling Store in a dry place protected from light. Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).

📋 Description 182 words ▾

11 DESCRIPTION Lopreeza 1 mg/0.5 mg is a single tablet for oral administration containing 1 mg of estradiol and 0.5 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin. Lopreeza 0.5 mg/0.1 mg is a single tablet for oral administration containing 0.5 mg of estradiol and 0.1 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), hydroxypropylcellulose, talc, magnesium stearate, hypromellose and triacetin.

Estradiol (E 2 ), an estrogen, is a white or almost white crystalline powder. Its chemical name is estra-1, 3, 5 (10)-triene-3, 17β-diol hemihydrate with the empirical formula of C 18 H 24 O 2 ,½ H 2 O and a molecular weight of 281.4. The structural formula of E 2 is as follows: Estradiol Norethindrone acetate (NETA), a progestin, is a white or yellowish-white crystalline powder.

Its chemical name is 17β-acetoxy-19-nor-17α -pregn-4-en-20-yn-3-one with the empirical formula of C 22 H 28 O 3 and molecular weight of 340.5. The structural formula of NETA is as follows: Norethindrone Acetate estradiol chem structure noreth acetate chem structure

💬 Information for Patients 161 words ▾

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information )

17.1Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2) ] .

17.2Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3) ] .

17.3Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting. Rx Only Lopreeza ® is a registered trademark owned by Amneal Pharmaceuticals ©2016 Amneal Pharmaceuticals Rev. 11-2017-03 For information contact: Amneal Pharmaceuticals 1-877-835-5472 www.amneal.com Manufactured by: Novo Nordisk A/S 2880 Bagsvaerd, Denmark Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807

🍼 Nursing Mothers 60 words ▾

8.3Nursing Mothers Lopreeza should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when Lopreeza is administered to a nursing woman.

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics Absorption Estradiol Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Lopreeza tablets, peak plasma estradiol concentrations are reached within 5 to 8 hours. The oral bioavailability of estradiol following administration of Lopreeza 1 mg/0.5 mg when compared to a combination oral solution is 53%.

Administration of Lopreeza 1 mg/0.5 mg with food did not modify the bioavailability of estradiol. Norethindrone Acetate After oral administration, norethindrone acetate is absorbed and transformed to norethindrone. Norethindrone reaches a peak plasma concentration within 0.5 to 1.5 hours after the administration of Lopreeza tablets.

The oral bioavailability of norethindrone following administration of Lopreeza 1 mg/0.5 mg when compared to a combination oral solution is 100%. Administration of Lopreeza 1 mg/0.5 mg with food increases norethindrone AUC 0-72 by 19% and decreases C max by 36%. The pharmacokinetic parameters of estradiol (E 2 ), estrone (E 1 ), and norethindrone (NET) following oral administration of 1 Lopreeza 1 mg/0.5 mg or 2 Lopreeza 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 3.

TABLE 3 PHARMACOKINETIC PARAMETERS AFTER ADMINISTRATION OF 1 TABLET OF LOPREEZA 1 MG/0.5 MG OR 2 TABLETS OF LOPREEZA

0.5MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMEN 1 x Lopreeza 1 mg/0.5 mg (n=24) 2 x Lopreeza 0.5 mg/0.1 mg (n=24) Mean a (%CV) b Mean a (%CV) b Estradiol c (E 2 ) AUC 0-t (pg/mL*h) 766.5 (48) 697.3 (53) C max (pg/mL) 26.8 (36) 26.5 (37) t max (h): median (range) 6.0 (0.5-16.0) 6.5 (0.5-16.0) t 1/2 (h) d 14.0 e (29) 14.5 f (27) Estrone c (E 1 ) AUC 0-t (pg/mL*h) 4469.1 (48) 4506.4 (44) C max (pg/mL) 195.5 (37) 199.5 (30) t max (h): median (range) 6.0 (1.0-9.0) 6.0 (2.0-9.0) t 1/2 (h) d 10.7 (44) g 11.8 (25) g Norethindrone (NET) AUC 0-t (pg/mL*h) 21043 (41) 8407.2 (43) C max (pg/mL) 5249.5 (47) 2375.4 (41) t max (h) : median (range) 0.7 (0.7-1.25) 0.8 (0.7-1.3) t 1/2 (h) 9.8 (32) h 11.4 (36) i AUC = area under the curve, 0 – last quantifiable sample C max = maximum plasma concentration, t max = time at maximum plasma concentration, t 1/2 = half-life, a geometric mean; b geometric % coefficient of variation; c baseline unadjusted data; d baseline unadjusted data; e n=18; f n=16; g n=13; h n=22; i n=21 Following continuous dosing with once-daily administration of Lopreeza 1 mg/0.5 mg,serum concentrations of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33 to 47% above concentrations following single dose administration.

Unadjusted circulating concentrations of E 2 , E 1 , and NET during Lopreeza 1 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b. Figure 1a: Mean Baseline-Uncorrected Estradiol and Estrone Serum Concentration-Time Profiles Following Multiple Doses of Lopreeza 1 mg/0.5 mg (N=24) Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of Lopreeza 1 mg/0.5 mg (N=24) Distribution Estradiol 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 to 2% is unbound. Norethindrone Acetate Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).

Metabolism Estradiol 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 reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics 11 words ▾

12.2Pharmacodynamics There are no pharmacodynamic data known for Lopreeza tablets.

🔬 Clinical Studies ~3 min read ▾

14 CLINICAL STUDIES

14.1Effects on Vasomotor Symptoms In a 12-week randomized clinical trial involving 92 subjects, Lopreeza 1 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Lopreeza 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2). Figure 2 Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Lopreeza 0.5 mg/0.1 mg, 0.5 mg E 2 /0.25 mg NETA, or placebo for 24 weeks of treatment.

The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Lopreeza 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E 2 /0.25 mg NETA groups compared to placebo. Figure 3 Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12 figure2 figure 3

14.2Effects on the Endometrium Lopreeza 1 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 subjects who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E 2 + 0.1 mg NETA (n=294), 1 mg E 2 + 0.25 mg NETA (n=291), and Lopreeza 1 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects.

The results of the 1 mg estradiol unopposed arm compared to Lopreeza 1 mg/0.5 mg are shown in Table 4. TABLE 4 INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND LOPREEZA 1 MG/0.5 MG IN A 12-MONTH STUDY 1 mg E 2 (n=296) Lopreeza 1 mg E 2 /0.5 mg NETA (n=295) 1 mg E 2 /0.25 mg NETA (n=291 ) 1 mg E 2 /0.1 mg NETA (n=294 ) No. of subjects with histological evaluation at the end of the study 247 241 251 249 No. (%) of subjects with endometrial hyperplasia at the end of the study 36 (14.6%) 1 (0.4%) 1 (0.4%) 2 (0.8%)

14.3Effects on Uterine Bleeding or Spotting During the initial months of therapy, irregular bleeding or spotting occurred with Lopreeza 1 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Lopreeza 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4). Figure 4 Patients Treated with Lopreeza 1 mg/0.5 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 Intent to Treat Population, LOCF Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown.

If data were missing, the bleeding value from the last reported day was carried forward (LOCF). In the clinical trial with Lopreeza 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5). Figure 5 Patients Treated with Lopreeza 0.5 mg/0.1 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent to Treat Population, LOCF figure 4 figure 5

14.4Effects on Bone Mineral Density The results of two randomized, multicenter, calcium-supplemented (500-1000 mg per day), placebo-controlled, 2 year clinical trials have shown that Lopreeza 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women (T-score > -2.0) were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo.) In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomi… [Excerpted — this section continues on DailyMed.]

🧪 Nonclinical Toxicology 35 words ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 32 words ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

📚 References 212 words ▾

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 ~3 min read ▾

Patient Information Lopreeza ® (lo-PREE-zuh) (estradiol/norethindrone acetate) Tablets Read this Patient Information before you start taking Lopreeza and each time you get a refill. 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 Lopreeza (a combination of estrogen and progestin)? Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function). Taking estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.

Taking estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older. Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia. Taking estrogen-alone may increase your chance of getting cancer of the uterus (womb).

Taking estrogen-alone may increase your chances of getting strokes or blood clots. Taking estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older. You and your healthcare provider should talk regularly about whether you still need treatment with Lopreeza.

What is Lopreeza? Lopreeza is a prescription medicine that contains two kinds of hormones, an estrogen and a progestin. What is Lopreeza used for?

Lopreeza is used after menopause to: reduce moderate to severe hot flushes Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 yrs 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 get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden, intense episodes of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need to take estrogens.

In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether or not you still need treatment with Lopreeza. treat moderate to severe menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with Lopreeza 1.0 mg/0.5 mg to treat these problems. If you use Lopreeza 1.0 mg/0.5 mg 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. help reduce your chances of getting osteoporosis (thin weak bones) If you use Lopreeza only to prevent osteoporosis from menopause, talk to your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.

You and your healthcare provider should talk regularly about whether you still need treatment with Lopreeza. Who should not take Lopreeza? Do not take Lopreeza if you have had your uterus (womb) removed (hysterectomy).

Lopreeza contains a progestin to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not take Lopreeza. Do not take Lopreeza if you: 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. currently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take Lopreeza. had a stroke or… [Excerpted — this section continues on DailyMed.]

📄 Recent Major Changes 10 words ▾

RECENT MAJOR CHANGES Warnings and Precautions, Malignant Neoplasm (5.2) 07/2017

📄 Package Label / Principal Display Panel 11 words ▾

PRINCIPAL DISPLAY PANEL LD dial

LD carton

HD dial

HD carton

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

About this NDC listing & data coverage

Finished prescription product
What data is (and isn’t) available for this NDC — tap to expand
NDC identity (package / product / labeler codes) ✓ Available
Labeler ✓ Available
Product & package description ✓ Available
Marketing category & status ✓ Available
Active ingredient / dosage form / route ✓ Available
FDA label (SPL via DailyMed) ✓ Available
Package photos — Not published for this NDC No photo available yet for this listing.
Inactive ingredients (structured) — Not published for this NDC The labeler did not submit a structured excipient list, or no SPL is available.
NADAC pharmacy acquisition price (CMS) — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey.
Orange Book / therapeutic-equivalence data ✓ Available
HCPCS J-code billing crosswalk — Not published for this NDC Most self-administered / retail products have no J-code — that is normal.
Medicaid utilization (CMS SDUD) — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold.
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Is this package still being marketed?
Yes, per the latest FDA NDC Directory data on this page: this package is listed as actively marketed, with no marketing end date reported by Amneal Pharmaceuticals NY LLC. Listing status can change — the directory data on this page refreshes weekly.
Who lists this product with the FDA?
Amneal Pharmaceuticals NY LLC is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 69238-1251-08 · Amneal 69238-1254-03 · Amneal →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.