Activella

Name: Activella

What is the most important information I should know about Activella (estradiol and norethindrone)?

Do not use if you are pregnant.

You should not use estradiol and norethindrone if you have had a hysterectomy, or if you have any of the following conditions: liver disease, unusual vaginal bleeding, a history of breast or uterine cancer, or if you have recently had a heart attack, stroke, or a blood clot.

Estradiol and norethindrone should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions.

Long-term use of this medicine may increase your risk of breast cancer, uterine cancer, heart attack, stroke, or blood clot. Talk with your doctor about your individual risk.

Do not take this medicine in larger amounts or for longer than recommended.

What should I discuss with my healthcare provider before taking Activella (estradiol and norethindrone)?

You should not use estradiol and norethindrone if you are allergic to it, or if you have:

  • a recent history of heart attack, stroke, or blood clots;

  • liver disease;

  • abnormal vaginal bleeding that a doctor has not checked;

  • a history of breast, uterine, or hormone-related cancer;

  • if you have had a hysterectomy; or

  • if you are pregnant.

To make sure this medicine is safe for you, tell your doctor if you have:

  • heart disease;

  • risk factors for coronary artery disease (such as diabetes, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, or if you have had a hysterectomy);

  • asthma;

  • diabetes;

  • epilepsy or other seizure disorder;

  • migraines;

  • porphyria;

  • lupus;

  • kidney disease;

  • gallbladder disease;

  • endometriosis or uterine fibroid tumors;

  • a thyroid disorder; or

  • high levels of calcium in your blood.

Long-term use of estradiol and norethindrone may increase your risk of breast cancer, uterine cancer, heart attack, stroke, or blood clot. Talk with your doctor about your individual risks before using this medicine long term.

Estradiol and norethindrone should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions.

FDA pregnancy category X: Do not use estradiol and norethindrone if you are pregnant. Tell your doctor right away if you become pregnant during treatment.

Estradiol and norethindrone can pass into breast milk. This medication may slow breast milk production. Do not use if you are breast-feeding a baby.

Uses For Activella

Estrogens and progestins are female hormones. They are produced by the body and are necessary for the normal sexual development of the female and for the regulation of the menstrual cycle during the childbearing years.

The ovaries begin to produce less estrogen after menopause (the change of life). This medicine is prescribed to make up for the lower amount of estrogen. Estrogens help relieve signs of menopause, such as hot flashes and unusual sweating, chills, faintness, or dizziness. Progestins help to regulate the effects of estrogens.

Estrogens are prescribed for several reasons:

  • to provide additional hormone when the body does not produce enough of its own, such as during menopause. They can also help to relieve a genital skin condition called vaginal or vulvar atrophy.
  • to help prevent weakening of bones (osteoporosis) in women past menopause.

Estrogens may also be used for other conditions as determined by your doctor.

There is no medical evidence to support the belief that the use of estrogens will keep the patient feeling young, keep the skin soft, or delay the appearance of wrinkles. Nor has it been proven that the use of estrogens during menopause will relieve emotional and nervous symptoms, unless these symptoms are caused by other menopausal symptoms, such as hot flashes or hot flushes.

Estrogens and progestins are available only with your doctor's prescription.

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.

Metabolic 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 ( Hypericumperforatum) 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.

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. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.

4. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.

5. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.

6. 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.

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.

How Supplied/Storage and Handling

How Supplied

Activella 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 60846-202-01). It is supplied as 28 tablets in a calendar dial pack dispenser.

Activella 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 60846-201-01). It is supplied as 28 tablets in a calendar dial pack dispenser.

Storage 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).

Patient information

Activella ® (AK-ti-vel-la)

(estradiol/norethindrone acetate)

Tablets

Read this Patient Information before you start taking Activella 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 Activella

(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 Activella.

What is Activella?

Activella is a prescription medicine that contains two kinds of hormones, an estrogen and a progestin.

What is Activella used for?

Activella 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 Activella.

  • 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 Activella 1.0 mg/0.5 mg to treat these problems. If you use Activella 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 Activella 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 Activella.

Who should not take Activella?

Do not take Activella if you have had your uterus (womb) removed (hysterectomy).

Activella 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 Activella.

Do not take Activella 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 Activella.

  • had a stroke or heart attack
  • currently have or have had blood clots
  • currently have or have had liver problems
  • have been diagnosed with a bleeding disorder
  • are allergic to Activella or any of its ingredients

See the list of ingredients in Activella at the end of this leaflet.

  • think you may be pregnant

Activella is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not take Activella if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before taking Activella?

Before you take Activella, tell your healthcare provider 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

Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or 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 taking Activella.

  • are breast feeding

The hormones in Activella can pass into your breast milk.

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

How should I take Activella?

  • Take Activella exactly as your healthcare provider tells you to take it.
  • Take 1 Activella at the same time each day.
  • You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with Activella.

Follow the instructions below to use your Activella Dispenser.

What are the possible side effects of Activella?

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
  • dementia
  • breast cancer
  • cancer of the lining of the uterus (womb)
  • cancer of the ovary
  • high blood pressure
  • high blood sugar
  • gallbladder disease
  • liver problems
  • changes in your thyroid hormone levels
  • enlargement of benign tumors (“fibroids”)

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

Less serious, but common side effects include:

  • headache
  • breast pain
  • irregular vaginal bleeding or spotting
  • stomach or abdominal cramps, bloating
  • nausea and vomiting
  • hair loss
  • fluid retention
  • vaginal yeast infection

These are not all the possible side effects of Activella. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or does not go away. You may report side effects to Gemini Laboratories, LLC at (855) 346-8326 or to FDA at 1-800-FDA-1088.

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

  • Talk with your healthcare provider regularly about whether you should continue taking Activella.
  • If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you.
  • The addition of a progestin 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 taking Activella.
  • 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 (breast x-ray), 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 for getting heart disease.

Ask your healthcare provider for ways to lower your chances for getting heart disease.

How should I store Activella?

  • Store Activella at room temperature between 68°F to 77°F (20°C to 25°C).
  • Store Activella in a dry place protected from light.

KEEP Activella and all medicines out of the reach of children.

General information about the safe and effective use of Activella.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Activella for conditions for which it was not prescribed. Do not give Activella to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Activella. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about Activella that is written for health professionals.

For more information go to www.Activella.com.

What are the ingredients in Activella?

Active ingredients: estradiol and norethindrone acetate

Inactive Ingredients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose, and triacetin.

The 0.5 mg/0.1 mg tablet also contains hydroxypropylcellulose.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Activella ® is a registered trademark owned by Novo Nordisk FemCare AG

The embossed (Apis) bull symbol on the tablets is a trademark of Novo Nordisk A/S.

©2000-2015 Novo Nordisk

Novo Nordisk Inc.

Gemini Laboratories, LLC

Bridgewater, NJ 08807, USA

www.gemini-labs.com

Manufactured by:

Novo Nordisk A/S

2880 Bagsvaerd,

Denmark

Uses of Activella

Activella is a prescription medication used after menopause to reduce moderate to severe hot flashes, treat moderate to severe menopausal changes in and around the vagina, and help reduce your chances of getting osteoporosis (thin weak bones). 

Activella is an estrogen and progestin combination indicated in a woman with a uterus.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

For the Consumer

Applies to estradiol / norethindrone: oral tablet

Other dosage forms:

  • transdermal patch extended release

Along with its needed effects, estradiol / norethindrone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking estradiol / norethindrone:

More common
  • Body aches or pain
  • chills or fever
  • cold or flu-like symptoms
  • difficulty breathing
  • headache
  • itching of the vagina or genital area
  • nonmenstrual vaginal bleeding
  • pain during sexual intercourse
  • thick, white vaginal discharge with no odor or with a mild odor
  • unusual tiredness or weakness
Incidence not known
  • Abdominal or stomach pain
  • blistering, peeling, or loosening of the skin
  • change in vaginal discharge
  • chest pain, discomfort, or tightness in chest
  • clay-colored stools
  • clear or bloody discharge from the nipple
  • confusion
  • dark urine
  • difficulty speaking
  • difficulty swallowing
  • dizziness or lightheadedness
  • double vision
  • fainting
  • fast heartbeat
  • inability to move the arms, legs, or facial muscles
  • inability to speak
  • joint or muscle pain
  • loss of appetite
  • lump in the breast or under the arm
  • nausea and vomiting
  • noisy breathing
  • pain in the ankles or knees
  • pain or discomfort in the arms, jaw, back, or neck
  • pain or feeling of pressure in the pelvis
  • pain, redness, or swelling in the arm or leg
  • painful, red lumps under the skin, mostly on the legs
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • problems with memory or speech
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • red, irritated eyes
  • redness or swelling of the breast
  • skin rash, hives, or itching
  • sores, ulcers, or white spots in the mouth or on the lips
  • sudden shortness of breath or troubled breathing
  • sweating
  • trouble recognizing objects
  • trouble thinking and planning
  • trouble walking

Some side effects of estradiol / norethindrone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Back pain
  • breast pain
  • cramps
  • crying
  • euphoria
  • mental depression
  • paranoia
  • quick to react or overreact emotionally
  • rapidly changing moods
  • trouble sleeping
  • weakness
  • weight gain
Incidence not known
  • Changes in appetite
  • changes in sexual ability, desire, drive, or performance
  • excess air or gas in the stomach or intestines
  • increased hair growth, especially on the face
  • patchy brown or dark brown discoloration of the skin
  • trouble wearing contact lenses

For Healthcare Professionals

Applies to estradiol / norethindrone: oral tablet, transdermal film extended release

Gastrointestinal

Gastrointestinal side effects have included nausea (8% to 11%), abdominal pain (6% to 7%), diarrhea (4% to 5%), flatulence (4% to 5%), and dyspepsia (1% to 5%).[Ref]

General

General side effects have included headache (18% to 20%), asthenia (8% to 12%), back pain (9% to 11%), flu syndrome (5% to 9%), pain (4% to 6%), and accidental injury (4% to 5%). Postmarketing side effects include increased weight.[Ref]

Genitourinary

Genitourinary side effects have included breast pain (25% to 31%), dysmenorrhea (20% to 21%), vaginitis (6% to 13%), menstrual disorder (6% to 12%), suspicious Papanicolaou smear (4% to 8%), and leukorrhea (5%). Endometrial thickening (10% to 4%) and vaginal hemorrhage (26% to 12%) have also been reported. Postmarketing side effects include endometrial hyperplasia, endocervical polyp, uterine leiomyomata, fallopian tube cyst, uterine spasms, and breast cancer.[Ref]

Local

Local side effects have included reactions at the application site (2% to 6%).[Ref]

Psychiatric

Psychiatric side effects have included nervousness (3% to 6%) and depression (3% to 6%).[Ref]

Respiratory

Respiratory side effects have included rhinitis (7% to 13%), respiratory disorder (7% to 12%), pharyngitis (4% to 10%), and sinusitis (4% to 9%).[Ref]

Cardiovascular

Cardiovascular side effects include postmarketing reports of hypertension and varicose veins.

Dermatologic

Dermatologic side effects include postmarketing reports of skin discoloration.

Hepatic

Hepatic side effects include postmarketing reports of jaundice cholestatic, cholelithiasis, gall bladder disorder, and increased transaminases.

Hypersensitivity

Hypersensitivity side effects include postmarketing reports of angioedema and hypersensitivity.

Nervous system

Nervous system side effects include postmarketing reports of affect lability, libido disorder, migraine, vertigo, and paraesthesia.

Some side effects of Activella may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Usual Adult Dose for Osteoporosis

Regimen 1 (Cyclic Combined Estrogen-Progestin Therapy): Conjugated estrogens 0.625 mg orally once a day AND Medroxyprogesterone acetate 5 mg orally once a day for 14 days per month.

-or-

Regimen 2 (Continuous Combined Estrogen-Progestin Therapy): Conjugated estrogens 0.3 mg orally once a day AND Medroxyprogesterone acetate 1.5 mg orally once a day or conjugated estrogens 0.625 mg orally once a day AND Medroxyprogesterone acetate 2.5 mg or 5 mg orally once a day.

Long-term therapy (for more than 5 years) is generally necessary in order to obtain substantive benefits in reducing the risk of bone fracture. Maximal benefits are obtained if estrogen therapy is initiated as soon after menopause as possible. The optimal duration of therapy has not been definitively determined.

In addition to hormonal therapy, adequate calcium intake is important for postmenopausal women who require treatment or prevention of osteoporosis. The average diet of older American women contains 400 to 600 mg of calcium per day. 1500 mg per day has been suggested as optimal intake. If dietary intake is insufficient to achieve 1500 mg per day, dietary supplementation may be useful in women who have no contraindication to calcium supplementation.

Usual Adult Dose for Atrophic Urethritis

Regimen 1 (Cyclic Combined Estrogen-Progestin Therapy): Conjugated estrogens 0.625 mg orally once a day AND Medroxyprogesterone acetate 5 mg orally once a day for 14 days per month.

-or-

Regimen 2 (Continuous Combined Estrogen-Progestin Therapy): Conjugated estrogens 0.45 mg orally once a day AND Medroxyprogesterone acetate 1.5 mg orally once a day or conjugated estrogens 0.625 mg orally once a day AND Medroxyprogesterone acetate 2.5 mg or 5 mg orally once a day.

In general, the duration of hormone therapy for the treatment of postmenopausal symptoms like atrophic vaginitis, kraurosis vulvae, or atrophic urethritis should be limited. Treatment for one to five years is generally sufficient.

Conjugated estrogens / medroxyprogesterone Breastfeeding Warnings

There are no data on the excretion of conjugated estrogens into human milk. However, a decrease in quality and quantity of milk is associated with the administration of estrogen to nursing women. The American Academy of Pediatrics considers estradiol, another estrogenic agent, to be compatible with breast-feeding. Medroxyprogesterone is excreted into breast milk. Lactation does not appear to be adversely affected by contraceptive use of medroxyprogesterone. The American Academy of Pediatrics considers the use of medroxyprogesterone to be compatible with breast-feeding. The manufacturer recommends that caution be used when administering conjugated estrogens-medroxyprogesterone to nursing women.

The excretion of medroxyprogesterone into breast milk was evaluated in 10 women who received medroxyprogesterone acetate 150 mg intramuscularly for contraception. Mean medroxyprogesterone milk concentrations ranged from approximately 8 ng/mL at one week to approximately 0.5 ng/mL at 12 weeks after the injection. The milk to maternal serum concentration ratio ranged from 0.12 to 2.60 (mean 0.88). Contraceptive use of medroxyprogesterone does not adversely affect the content or volume of breast milk. In addition, progestin during lactation may promote longer duration of lactation. Long-term follow-up studies of up to eight years duration have failed to document adverse development effects due to exposure to medroxyprogesterone in breast milk.

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