LYLLANA Estradiol .1 mg/d Patch, Extended Release, 8 pouches
Other active recalls for Estradiol (different manufacturers) — 4 · tap to view
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Radioactive Diagnostic Agent class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Transdermal estradiol (Climara®, Minivelle®, Vivelle-Dot®) is used to treat hot flashes (hot flushes; sudden feelings of mild or intense body heat) in women who are experiencing menopause (change of life; the end of monthly menstrual periods). Transdermal estradiol (Climara®, Vivelle-Dot®) is also used to treat vaginal dryness, itching, and burning in women who are experiencing menopause. Transdermal estradiol (Climara®, Menostar®, Minivelle®, Vivelle-Dot®) is also used to prevent osteoporosis (a condition in which the bones become thin and weak and break easily) in women who are experiencing...
Read the full MedlinePlus article ↗- Estradiol is a form of estrogen — the main female sex hormone. When estrogen levels fall after menopause (or due to other conditions like ovarian failure), you can get symptoms lik...
- What exactly is estradiol and why has my doctor prescribed it?
- Apply the patch to a clean, dry area of skin — usually the lower abdomen. Never put it on your breasts. Press it firmly in place and leave it on for the full wear period — once a w...
- How do I use my estradiol patch correctly?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Estradiol — tap one for details:
Estradiol may be associated with lower levels of 5 nutrients — worth a chat with your pharmacist, not a cause for alarm.
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Ask a licensed pharmacist directly — free, answered by our team.
💊 What it looks like
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🧪 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 83D19O7250
A silicone-based polymer that forms a smooth, water-repellent coating. It's used in topical products as a skin protectant and to improve spreadability and texture.
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UNII E107L85C40
Dipropylene glycol is a clear liquid made from propylene glycol. It acts as a solvent and humectant in medicines, helping dissolve active ingredients and retain moisture in the formulation.
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UNII 172F2WN8DV
A fatty alcohol derived from animal or plant oils. It acts as an emollient and helps stabilize emulsions, allowing oil and water to mix evenly in the medication.
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UNII U725QWY32X
Povidone K30 is a synthetic polymer made from petroleum. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in the stomach so the medicine can be absorbed.
4 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.Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
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💲 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 | $8.229 | $65.83 / 8 d |
| Medicaid paysCMS SDUD · 12 mo | $6.91 | $55.29 / 8 d |
| Medicare drug plans payPart D · Q2 2026 | $7.64 | $61.08 / 8 d |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Estradiol .1 mg/d 00378-4623-26 | Mylan | 8 patches | $8.229 | AB3 | Availability likely | — |
| Estradiol .1 mg/d 00378-4640-26 | Mylan | 8 patches | $8.229 | AB1 | Availability likely | — |
| Lyllana .1 mg/dthis 65162-0228-08 | Amneal | 8 pouches | $8.229 | AB3 | Availability likely | — |
| Dotti .1 mg/d 65162-0997-08 | Amneal | 8 pouches | $8.229 | AB1 | Availability likely | — |
| Estradiol .1 mg/d 68968-3410-08 | Noven | 8 pouches | $8.229 | AB3 | Availability likely | — |
| Estradiol .1 mg/d 70710-1195-08 | Zydus | 8 patches | $8.229 | AB1 | Availability likely | — |
| Minivelle .1 mg/d 68968-6610-08 | Noven | 8 pouches | $11.577 | AB3 | Availability likely | +41% |
| Estradiol .1 mg/d 00378-3352-99 | Mylan | 4 patches | $12.361 | AB2 | Availability likely | +50% |
| Estradiol Transdermal System .1 mg/d 00781-7104-54 | Sandoz | 4 patches | $12.361 | AB2 | Availability likely | +50% |
| Climara .1 mg/d 50419-0452-04 | Bayer | 4 patches | $18.310 | AB2 | Availability likely | +123% |
| Vivelle-Dot .1 mg/d 66758-0149-83 | Sandoz | 8 patches | $18.394 | AB1 | Availability likely | +124% |
| Estradiol .1 mg/d 00781-7167-40 | Sandoz | 24 patches | — | AB1 | Discontinued | — |
| Estradiol .1 mg/d 69238-1296-07 | Amneal | 8 pouches | — | AB3 | FDA listed | — |
| Estradiol .1 mg/d 69238-1633-07 | Amneal | 8 pouches | — | AB1 | FDA listed | — |
| Estradiol .1 mg/d 70771-1567-08 | Zydus | 8 patches | — | AB1 | FDA listed | — |
| Dotti .1 mg/d 72162-2036-02 | Bryant | 8 pouches | — | AB1 | FDA listed | — |
| estradiol .1 mg/d 70771-1406-04 | Zydus | 4 patches | — | AB2 | FDA listed | — |
| Estradiol .1 mg/d 50090-7984-00 | A-S | 4 pouches | — | AB2 | FDA listed | — |
| estradiol .1 mg/d 68382-0329-04 | Zydus | 4 patches | — | AB2 | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
🗺️ Medicaid utilization & spend
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Reporter sex
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 65162-0228-08 You're viewing this | 8 POUCH in 1 CARTON (65162-228-08) / 1 d in 1 POUCH (65162-228-04) | 2020-09-30 | Active |
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER 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 a dequate 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 (5.2) ] .
Cardiovascular Disorders and Probable Dementia The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.1) and Clinical Studies (14.3) ] . The WHI Memory Study (WHIMS) estrogen-alone ancillary study of 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 (5.3), Use in Specific Populations (8.5) , and Clinical Studies (14.4) ] . Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.3 , 14.4) ] . 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 route of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.
Prescribe e strogens 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 Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The WHI estrogen plus progestin substudy reported increased risks of 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 CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1) and Clinical Studies (14.3) ] .
The WHIMS estrogen plus progestin ancillary study of the 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 (5.3), Use in Specific Populations (8.5) , and Clinical Studies (14.4) ] . Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.3 , 14.4)] .
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 (14.3) ] . Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the 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 progestogen products is…
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE LYLLANA is indicated for: LYLLANA ® is an estrogen indicated for: Treatment of moderate to severe vasomotor symptoms due to menopause ( 1.1 ) Prevention of postmenopausal osteoporosis ( 1.2 ) Limitations of Use When prescribing solely for the treatment of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.
1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause
1.2Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus, does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions (5.2, 5.14) ] .
Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. Start therapy with LYLLANA ® 0.0375 mg per day applied to the skin twice weekly 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 LYLLANA 0.025 mg per day applied to the skin twice weekly for the prevention of postmenopausal osteoporosis. The dose may be adjusted as necessary (2.2) Place LYLLANA on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply LYLLANA to the breasts (2.3)
2.1Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Start therapy with LYLLANA 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on clinical response. Attempt to taper or discontinue LYLLANA at 3 to 6 month intervals.
2.2 Prevention of Postmenopausal Osteoporosis due to Menopause
2.3Application Instructions Place the adhesive side of LYLLANA on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply LYLLANA to the breasts. Replace LYLLANA twice weekly (every 3 to 4 days).
Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site. Select an area for application that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off.
Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact with the skin, especially around the edges. In the event that a system falls off, reapply the same system or apply a new system to another location.
In either case, continue the original treatment schedule. If a woman has forgotten to apply LYLLANA, have her apply a new system as soon as possible. Apply the new system on the original treatment schedule.
The interruption of treatment in women taking LYLLANA might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day. Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day (3)
⛔ Contraindications ▾
4 CONTRAINDICATIONS LYLLANA is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2) ]. Breast cancer or a history of breast cancer [see Warnings and Precautions (5.2) ]. Estrogen-dependent neoplasia [see Warnings and Precautions (5.2 )].
Active DVT, PE, or a history of these conditions [see Warnings and Precautions (5.1) ]. Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [see Warnings and Precautions (5.1) ] . Known anaphylactic reaction, angioedema, or hypersensitivity to LYLLANA Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer (4, 5.2 ) Estrogen-dependent neoplasia (4, 5.2 ) Active DVT, PE, or a history of these conditions (4, 5.1 ) Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions (4, 5.1 ) Known anaphylactic reaction, angioedema, or hypersensitivity to LYLLANA (4) Hepatic impairment or disease (4, 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gallbladder 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 Disorder Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin 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 obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus). Stroke 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, respectively).
The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.3) ] . 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 The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving 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, (14.3) ] . The increase in risk was demonstrated after the first year and persisted. 1 Immediately discontinue estrogen plus progestogen 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 The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving 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) [see Clinical Studies, (14.3) ] . The increase in risk was demonstrated after the first year and persisted.¹ Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected.
Coronary Heart Disease The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies (14.3) ] . Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) of CHD events in those women receiving daily CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years).
1 The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of CHD events 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 (14.3) ] . 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)…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ] Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ] The most common adverse reactions (greater than or equal to 5 percent) with LYLLANA are: headache, breast tenderness, back pain, pain in limb, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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. There were no clinical trials conducted with LYLLANA. LYLLANA is bioequivalent to Vivelle ® .
The following adverse reactions are reported with Vivelle therapy: Table 1: Summary of Most Frequently Reported Adverse Reactions (Vivelle versus Placebo) Regardless of Relationship Reported at a Frequency ≥5 Percent Vivelle 0.025 mg/day † (N=47) N (%) Vivelle 0.0375 mg/day † (N=130) N (%) Vivelle 0.05 mg/day † (N=103) N (%) Vivelle 0.075 mg/day † (N=46) N (%) Vivelle 0.1 mg/day † (N=132) N (%) Placebo (N=157) N (%) Gastrointestinal disorders Constipation 2 (4.3) 5 (3.8) 4 (3.9) 3 (6.5) 2 (1.5) 4 (2.5) Dyspepsia 4 (8.5) 12 (9.2) 3 (2.9) 2 (4.3) 0 10 (6.4) Nausea 2 (4.3) 8 (6.2) 4 (3.9) 0 7 (5.3) 5 (3.2) General disorders and administration site conditions*** Influenza-like illness 3 (6.4) 6 (4.6) 8 (7.8) 0 3 (2.3) 10 (6.4) Pain NOS* 0 8 (6.2) 0 2 (4.3) 7 (5.3) 7 (4.5) Infections and infestations Influenza 4 (8.5) 4 (3.1) 6 (5.8) 0 10 (7.6) 14 (8.9) Nasopharyngitis 3 (6.4) 16 (12.3) 10 (9.7) 9 (19.6) 11 (8.3) 24 (15.3) Sinusitis NOS* 4 (8.5) 17 (13.1) 13 (12.6) 3 (6.5) 7 (5.3) 16 (10.2) Upper respiratory tract infection NOS* 3 (6.4) 8 (6.2) 11 (10.7) 4 (8.7) 6 (4.5) 9 (5.7) Investigations Weight increased 4 (8.5) 5 (3.8) 2 (1.9) 2 (4.3) 0 3 (1.9) Musculoskeletal and connective tissue disorders Arthralgia 0 11 (8.5) 4 (3.9) 2 (4.3) 5 (3.8) 9 (5.7) Back pain 4 (8.5) 10 (7.7) 9 (8.7) 4 (8.7) 14 (10.6) 10 (6.4) Neck pain 3 (6.4) 4 (3.1) 4 (3.9) 0 6 (4.5) 2 (1.3) Pain in limb 0 10 (7.7) 7 (6.8) 2 (4.3) 6 (4.5) 9 (5.7) Nervous system disorders Headache NOS* 7 (14.9) 35 (26.9) 32 (31.1) 23 (50.0) 34 (25.8) 37 (23.6) Sinus headache 0 12 (9.2) 5 (4.9) 5 (10.9) 2 (1.5) 8 (5.1) Psychiatric disorders Anxiety NEC** 3 (6.4) 5 (3.8) 0 0 2 (1.5) 4 (2.5) Depression 5 (10.6) 4 (3.1) 7 (6.8) 0 4 (3.0) 6 (3.8) Insomnia 3 (6.4) 6 (4.6) 4 (3.9) 2 (4.3) 2 (1.5) 9 (5.7) Reproductive system and breast disorders Breast tenderness 8 (17.0) 10 (7.7) 8 (7.8) 3 (6.5) 17 (12.9) 0 Dysmenorrhea 0 0 0 3 (6.5) 0 0 Intermenstrual bleeding 3 (6.4) 9 (6.9) 6 (5.8) 0 14 (10.6) 7 (4.5) Respiratory, thoracic and mediastinal disorders Sinus congestion 0 4 (3.1) 3 (2.9) 3 (6.5) 6 (4.5) 7 (4.5) Vascular disorders Hot flushes NOS* 3 (6.4) 0 3 (2.9) 0 0 6 (3.8) Hypertension NOS* 2 (4.3) 0 3 (2.9) 0 0 2 (1.3) † Represents milligrams of estradiol delivered daily by each system *NOS represents not otherwise specified **NEC represents not elsewhere classified ***Application site erythema and application site irritation were observed in 3.2% or less of patients across treatment groups.
During the clinical pharmacology studies with LYLLANA, 35 percent or less of subjects experienced barely perceptible erythema. No transdermal systems were removed due to irritation. Three subjects (2.2 percent) reported mild discomfort while wearing LYLLANA (N=136).
6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of LYLLANA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS 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 may result in adverse reactions. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration.
( 7 )
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary LYLLANA is not indicated for use in pregnancy. There are no data with the use of LYLLANA in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
8.2Lactation Risk Summary Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LYLLANA and any potential adverse effects on the breastfed child from LYLLANA or from the underlying maternal condition.
8.4Pediatric Use LYLLANA is not indicated for use in pediatric patients. 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 LYLLANA to determine whether those over 65 years of age differ from younger subjects in their response to LYLLANA. The Women’s Health Initiative Studies 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 (14.3) ] . 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) , and Clinical Studies (14.3) ] .
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 probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.4) ] . 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 (14.3) ] .
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary LYLLANA is not indicated for use in pregnancy. There are no data with the use of LYLLANA in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
🧒 Pediatric Use ▾
8.4Pediatric Use LYLLANA 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 LYLLANA to determine whether those over 65 years of age differ from younger subjects in their response to LYLLANA. The Women’s Health Initiative Studies 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 (14.3) ] . 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) , and Clinical Studies (14.3) ] .
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 probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.4) ] . 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 (14.3) ] .
🆘 Overdosage ▾
10 OVERDOSAGE Overdosage of estrogen 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 LYLLANA 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 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 follicle stimulating hormone (FSH) through a negative feedback mechanism.
Estrogens act to reduce the elevated concentrations of these hormones seen in postmenopausal women.
12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to LYLLANA nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.
12.3Pharmacokinetics Absorption In a single-dose, two way-crossover clinical study conducted in 96 healthy, non-smoking postmenopausal women under fed condition, LYLLANA (0.1 mg per day) was bioequivalent to Vivelle (0.1 mg per day) based on estradiol exposure (AUC 0-84 ) and estradiol peak concentration (C max ) following a single-dose on the lower abdomen for 84 hours. Estradiol pharmacokinetics were characterized in a separate open-label, single-center, randomized, single-dose, three-way crossover study conducted in 36 healthy, non-smoking postmenopausal women (aged 40 to 65 years).
LYLLANA transdermal systems delivering nominal estradiol of approximately 0.025 mg, 0.05 mg, and 0.1 mg per day were applied to the lower abdomen under fed state in a crossover fashion for 84 hours. The mean estradiol pharmacokinetics parameters are summarized in Table 2. AUC and C max are dose proportional from 0.025 mg to 0.1 mg per day.
Table 2: Mean (SD) Serum Pharmacokinetic Parameters of Baseline-Uncorrected Estradiol following a Single Dose of LYLLANA (N=36) Parameter 0.1 mg/day 0.05 mg/day 0.025 mg/day AUC 84 (pg·hr/mL) 5875 (1857) 3057 (980) 1763 (600) AUC 120 (pg·hr/mL) 6252 (1938) 3320 (1038) 1979 (648) C max (pg/mL) 117 (39.3) 56.6 (17.6) 30.3 (11.1) T max (hr) a 24.0 (8 to 60) 24.0 (8 to 60) 36.0 (8 to 84) a Median (minimum-maximum) Figure 1 illustrates the mean baseline-uncorrected estradiol serum concentrations of LYLLANA at three different strengths.
Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of LYLLANA 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (Treatment C) (N=36) Distribution 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. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin.
Metabolism 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…
🧬 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 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 follicle stimulating hormone (FSH) through a negative feedback mechanism.
Estrogens act to reduce the elevated concentrations of these hormones seen in postmenopausal women.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1How Supplied LYLLANA (estradiol transdermal system, USP), 0.025 mg per day - each 1.89 cm 2 system contains 0.314 mg of estradiol, USP for nominal* delivery of 0.025 mg of estradiol, USP per day. Patient Calendar Pack of 8 Systems…………………………………..NDC 65162-126-08 LYLLANA (estradiol transdermal system, USP), 0.0375 mg per day - each 2.83 cm 2 system contains 0.470 mg of estradiol, USP for nominal* delivery of 0.0375 mg of estradiol, USP per day. Patient Calendar Pack of 8 Systems…………………………………..NDC 65162-148-08 LYLLANA (estradiol transdermal system, USP), 0.05 mg per day - each 3.78 cm 2 system contains 0.627 mg of estradiol, USP for nominal* delivery of 0.05 mg of estradiol, USP per day.
Patient Calendar Pack of 8 Systems………………………………….NDC 65162-149-08 LYLLANA (estradiol transdermal system, USP), 0.075 mg per day - each 5.66 cm 2 system contains 0.940 mg of estradiol, USP for nominal* delivery of 0.075 mg of estradiol, USP per day. Patient Calendar Pack of 8 Systems………………………………….NDC 65162-150-08 LYLLANA (estradiol transdermal system, USP), 0.1 mg per day - each 7.55 cm 2 system contains 1.253 mg of estradiol, USP for nominal* delivery of 0.1 mg of estradiol, USP per day. Patient Calendar Pack of 8 Systems………………………………….NDC 65162-228-08 * See Description
16.2Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not store unpouched. Apply immediately upon removal from the protective pouch.
Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.
📋 Description ▾
11 DESCRIPTION LYLLANA (estradiol transdermal system, USP), contains estradiol, USP in a multipolymeric adhesive. The system is designed to release estradiol, USP continuously upon application to intact skin. Five dosage strengths of LYLLANA are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol, USP per day via the skin.
Each corresponding system has an active surface area of 1.89, 2.83, 3.78, 5.66, or 7.55 cm 2 and contains 0.314, 0.470, 0.627, 0.940, or 1.253 mg of estradiol USP, respectively. The composition of the systems per unit area is identical. Estradiol, USP is a white to practically white powder, chemically described as estra-1,3,5 (10)-triene-3,17β-diol.
The structural formula is The molecular formula of estradiol, USP is C 18 H 24 0 2 . The molecular weight is 272.39 LYLLANA is comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) polyester and ethylene vinyl acetate copolymer film (2) an adhesive formulation containing estradiol USP, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used.
The active component of the system is estradiol, USP. The remaining components of the system are pharmacologically inactive. Meets USP Drug Release Test 6. formula 3 layers
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Vaginal Bleeding Inform postmenopausal women to report unusual vaginal bleeding to their healthcare providers as soon as possible [see Warnings and Precautions (5.2) ] . Possible Serious Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] .
Possible Common Adverse Reactions with Estrogen-Alone Therapy Inform postmenopausal women of less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting. *All trademarks are the property of their respective owners. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 05-2024-04