PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Package Label - Principal Display Panel – 0.1mg Carton

NDC 68968-6610-8

0.1 mg/day

Minivelle**®**

(estradiol transdermal system)

Delivers 0.05 mg/day

Twice-Weekly

Rx Only

Includes 8 Systems

Open Here

Contents: 8 Systems

Rx Only

Each 6.6 cm2 system contains 1.65 mg of estradiol USP.

Inactive components: acrylic adhesive, silicone adhesive, oleyl alcohol, dipropylene glycol, povidone, polyolefin laminate backing, polyester release liner.

For Transdermal Use Only

Important: Package not child-resistant.

Apply immediate upon removal from pouch.

Do not store unpouched.

Store at 20°C to 25°C (68°F to 77°F).

[See USP Controlled Room Temperature].

Dosage and Administration: Apply twice-weekly. See package insert.

N3 68968-6610-8 5

302360-4

Noven

Your application schedule

Determine which 2 days of the week you will change your patch and then mark them on this calender

º Sunday/Wednesday º Thursday/Sunday

º Monday/Thursday º Friday/Monday

º Tuesday/Friday º Saturday/Tuesday

º Wednesday/Saturday

As a handy reminder of your application schedule, keep this tear out with you

Pull here for your Minivelle**®**** patches**

0.1 mg/day

Mfd. by: Noven Pharmaceuticals, Inc.

Miami, Florida 33186

Dist. by: Noven Therapeutics, LLC

Miami, Florida 33186

0.1 mg/day

Minivelle**®**

(estradiol transdermal system)

Delivers 0.025 mg/day

01440

302351-4

LOT/EXP

GTIN: 00368968661085

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RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

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DESCRIPTION SECTION

11 DESCRIPTION

MINIVELLE (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin.

Five dosage strengths of MINIVELLE are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via the skin. Each corresponding system has an active surface area of 1.65, 2.48, 3.30, 4.95, or 6.6 cm2 and contains 0.41, 0.62, 0.83, 1.24, or 1.65 mg of estradiol USP, respectively. The composition of the systems per unit area is identical.

Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17β-diol.

The structural formula is

The molecular formula of estradiol is C18H2402. The molecular weight is 272.39

MINIVELLE is comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a polyolefin laminate backing (2) an adhesive formulation containing estradiol, 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. The remaining components of the system are pharmacologically inactive.

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INDICATIONS & USAGE SECTION

Highlight: MINIVELLE® 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 INDICATIONS AND USAGE

MINIVELLE is indicated for:

1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause

1.2 Prevention 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 & ADMINISTRATION SECTION

Highlight: Start therapy with MINIVELLE® 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 MINIVELLE 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 MINIVELLE on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply MINIVELLE to the breasts (2.3)

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.

2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

Start therapy with MINIVELLE 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on clinical response. Attempt to taper or discontinue MINIVELLE at 3 to 6 month intervals.

2.2 Prevention of Postmenopausal Osteoporosis due to Menopause

2.3 Application Instructions

Place the adhesive side of MINIVELLE on a clean, dry area on the lower abdomen (below the umbilicus) or buttocks. Do not apply MINIVELLE to the breasts.

Replace MINIVELLE twice weekly (every 3-4 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 MINIVELLE, 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 MINIVELLE might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day (3)

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.

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CONTRAINDICATIONS SECTION

Highlight: * 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 MINIVELLE (4)
• Hepatic impairment or disease (4, 5.10)
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4)

4 CONTRAINDICATIONS

MINIVELLE 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 MINIVELLE
• Hepatic impairment or disease
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

BOXED WARNING SECTION

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA,

and BREAST CANCER

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DRUG INTERACTIONS SECTION

Highlight: Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. (7)

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.

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OVERDOSAGE SECTION

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 MINIVELLE therapy with institution of appropriate symptomatic care.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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.

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INFORMATION FOR PATIENTS SECTION

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 Warning 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.

SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION

MINIVELLE (MIN-ee-vell)

(estradiol transdermal system)

Read this Patient Information before you start using MINIVELLE 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 MINIVELLE?

MINIVELLE is a prescription medicine patch (transdermal system) that contains the estrogen hormone estradiol. When applied to the skin, estradiol is absorbed through the skin into the bloodstream.

What is MINIVELLE**®**** used for?**

MINIVELLE is used after menopause to:

*Reduce moderate to severe hot flashes
Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.”
When estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild and they will not need estrogens. In other women, symptoms can be more severe.

*Help reduce your chances of getting osteoporosis (thin weak bones)
Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use MINIVELLE only to prevent osteoporosis due to menopause, talk with 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 should continue treatment with MINIVELLE.

Who should not use MINIVELLE? Do not start using MINIVELLE 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.

*have been diagnosed with a bleeding disorder *currently have or have had certain cancers
Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use MINIVELLE.

• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems *are allergic to MINIVELLE or the ingredients in it. See the list of ingredients in MINIVELLE at the end of this leaflet.

Before you use MINIVELLE, tell your healthcare provider about all of your medical conditions, including if you:

*have any unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

*have any other medical conditions that may become worse while you are using MINIVELLE
Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), diabetes, epilepsy (seizures), migraine, endometriosis, lupus, angioedema (swelling of the face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

*are going to have surgery or will be on bed rest
Your healthcare provider will let you know if you need to stop using MINIVELLE.

*are pregnant or think you may be pregnant.
MINIVELLE is not for pregnant women.

*are breast feeding
The hormone in MINIVELLE can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Some medicines may affect how MINIVELLE works. MINIVELLE may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use MINIVELLE?

For detailed instructions, see the step-by-step instructions for using MINIVELLE at the end of this Patient Information

• Use MINIVELLE exactly as your healthcare provider tells you to use it
• MINIVELLE is for skin use only
• Change your MINIVELLE patch 2 times a week or every 3 to 4 days
• Apply your MINIVELLE patch to a clean, dry area on your lower abdomen or buttocks. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin
• Apply your MINIVELLE patch to a different area of your abdomen or your buttocks each time. Do not use the same application site 2 times in the same week.
• Do not apply MINIVELLE to your breasts
• If you forget to apply a new MINIVELLE patch, apply a new patch as soon as possible.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with MINIVELLE.

How to Change MINIVELLE

• When changing the patch, peel off the used patch slowly from the skin.
• After removal of MINIVELLE if any adhesive residue remains on your skin, allow the area to dry for 15 minutes. Then, gently rub the area with oil or lotion to remove the adhesive from your skin
• Apply the new patch to a different area of your abdomen or buttocks. This area must be clean, dry, cool and free of powder, oil or lotion.

What are the possible side effects of MINIVELLE?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

• heart attack
• stroke
• blood clots
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• dementia
• high or low blood calcium
• gallbladder disease
• visual abnormalities
• high blood pressure
• high levels of fat (triglyceride) in your blood
• liver problems
• changes in your thyroid hormone levels
• fluid retention
• cancer changes of endometriosis
• enlargement of benign tumors of the uterus (“fibroids”)
• worsening of swelling of face and tongue (angioedema) in women with a history of angioedema

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision or speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue
• swelling of face and tongue with or without red, itchy bumps

Common side effects of MINIVELLE include:

• headache
• breast pain
• irregular vaginal bleeding or spotting
• stomach or abdominal cramps, bloating
• nausea and vomiting
• hair loss
• fluid retention
• vaginal yeast infection
• redness and/or irritation at patch placement site

These are not all the possible side effects of MINIVELLE. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away. You may report side effects to Noven at 1-800-455-8070 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with MINIVELLE?

• Talk with your healthcare provider regularly about whether you should continue using MINIVELLE.
• If you have a uterus, talk to your healthcare provider about whether the addition of a progestogen is right for you. In general, the addition of a progestogen is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).
• See your healthcare provider right away if you get vaginal bleeding while using MINIVELLE.
• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease.

How should I store and throw away used MINIVELLE patches?

• Store MINIVELLE at room temperature 68°F to 77°F (20°C to 25°C)
• Do not store MINIVELLE patches outside of their pouches. Apply immediately upon removal from the protective pouch
• Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet

KEEP MINIVELLE and all other medicines out of the reach of children

General information about safe and effective use of MINIVELLE

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use MINIVELLE for conditions for which it was not prescribed. Do not give MINIVELLE to other people, even if they have the same symptoms you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about MINIVELLE that is written for health professionals. You can get more information by calling Noven Pharmaceuticals, Inc. at 1-800-455-8070.

What are the ingredients in MINIVELLE?

**Active ingredient:**estradiol

**Inactive ingredients:**Polyolefin laminate backing, acrylic and silicone adhesives, oleyl alcohol, NF, povidone, USP and dipropylene glycol and a polyester release liner

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INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USE

MINIVELLE**®** (MIN-ee-vell)

(estradiol transdermal system)

Read this PATIENT INFORMATION before you start using MINIVELLE 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.

You will need the following supplies**(See Figure A)**.

Figure A

Step 1: Pick the days you will change your patch.

• You will need to change your patch 2 times a week or every 3 to 4 days. Use the calendar printed inside your carton to choose the 2 days you will change your patch**(See Figure B)**. *Remember to change your patch on the same 2 days you marked on your calendar. If you forget to change your patch on the correct date, apply a new patch as soon as you remember, and continue to follow your original schedule

Figure B

Step 2. Remove the MINIVELLE patch from the pouch.

• Remove the patch from its protective pouch by tearing at the notch (do not use scissors,** See Figure C**).
• Do not remove your patch from the protective pouch until you are ready to apply it

Figure C

Step 3. Remove half of the adhesive liner (See Figure D).

Figure D

Step 4. Placing the patch on your skin.

• Hold the part of the patch that still has the adhesive liner on it *Avoid touching the sticky half of the patch with your fingers
• Apply the exposed sticky half of the patch to 1 of the areas of skin shown below**(See Figures E and F)**.

Note:

• Avoid the waistline, since clothing and belts may cause the patch to be rubbed off
• Do not apply the patch to your breasts
• Only apply the patch to skin that is clean, dry, and free of any powder, oil, or lotion
• You should not apply the patch to injured, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos, or that is very hairy)

Step 5: Press the patch firmly onto your skin.

• Remove the remaining half of the adhesive liner and press the entire patch into place with the palm of your hand for 10 seconds
• Rub the edges of the patch with your fingers to make sure that it will stick to your skin**(See Figure G)**.

Figure G

Note:

• Showering will not cause your patch to fall off
• If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area**(See Figures E and D)** and continue to follow your original placement schedule
• If you stop using your MINIVELLE patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, and recurrence of symptoms

Step 6: Throwing away your used patch.

• When it is time to change your patch, remove the old patch before you apply a new patch
• To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Manufactured by:
Noven Pharmaceuticals Inc.
Miami, FL 33186

Approved (02/2024)

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REFERENCES SECTION

15 REFERENCES

1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357–365.
3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006; 166:772-780.
4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.
5. 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.
6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.
9. 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.
10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

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