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Estradiol/norethindrone is used to relieve hot flashes, night sweats, and vaginal changes due to menopause, to prevent osteoporosis after menopause, or raise estrogen levels when the ovaries are not working properly or removed. Common side effects are nausea and headache. Before using estradiol/norethindrone, make sure to tell your health care provider about any health conditions you have or medicines you are taking. Get emergency help if you have trouble breathing, chest pain, or vision changes. This medicine is available as a tablet that you swallow or a patch that you apply to your skin.

Uses

What is estradiol/norethindrone used for?

Estradiol/norethindrone is commonly used for the following conditions.

These uses may vary depending on the specific estradiol/norethindrone product prescribed. 

Estradiol/norethindrone may also be used for other conditions as determined by your health care provider.

How does estradiol/norethindrone work (mechanism of action)?

Estradiol/norethindrone contains two kinds of hormones: estradiol (an estrogen) and norethindrone (a progestin). Estradiol works by replacing estrogen, a hormone your body makes less of during menopause. Norethindrone is a progestin hormone that helps balance the effect of estrogen, decreasing the chance of uterine cancer while taking an estrogen-containing medicine.

How is estradiol/norethindrone supplied (dosage forms)?

Brands and other names

  • Activella
  • Amabelz
  • CombiPatch
  • Lopreeza
  • Mimvey

Dosage forms and strengths

  • 0.5 mg/0.1 mg, 1 mg/0.5 mg oral tablets
  • 0.05 mg/0.14 mg/day, 0.05 mg/0.025 mg/day transdermal patches

How should I store estradiol/norethindrone?

Oral Tablets. Estradiol/norethindrone tablets should be stored at room temperature, between 68 F and 77 F (20 C and 25 C). It can be exposed to temperatures between 59 F and 86 F (15 C and 30 C) for shorter periods of time, such as when transporting it. Store in a cool, dry place. Protect from light. 

Topical Patch. Estradiol/norethindrone patches should be stored in the refrigerator between 36 F and 46 F (2 C and 8 C). Do not store the patches in areas where extreme temperatures can occur. Do not remove estradiol/norethindrone patches from their pouches until ready to use. Apply the patch right away after removing it from the protective pouch. 

Side Effects

What are the most common side effects of estradiol/norethindrone?

The most common side effects of estradiol/norethindrone are listed below. Tell your health care provider if you have any of these side effects that bother you.

  • Headache
  • Nausea, vomiting, or diarrhea
  • Stomach cramps or bloating
  • Trouble sleeping
  • Mood changes
  • Weight gain
  • Breast pain or tenderness
  • Unusual vaginal bleeding or spotting 
  • Vaginal yeast infection 
  • Hair loss
  • Skin irritation, redness, and other application site reactions (topical patch)
  • Fluid retention (see below)

There may be other side effects of estradiol/norethindrone that are not listed here. Contact your health care provider if you think you are having a side effect of a medicine. In the U.S., you can report side effects to the FDA at www.fda.gov/medwatch or by calling 800-FDA-1088. In Canada, you can report side effects to Health Canada at www.health.gc.ca/medeffect or by calling 866-234-2345.

What are the serious side effects of estradiol/norethindrone?

While less common, the most serious side effects of estradiol/norethindrone are described below, along with what to do if they happen.

Severe Allergic Reactions. Estradiol/norethindrone may cause allergic reactions, which can be serious. Stop using estradiol/norethindrone and get help right away if you have any of the following symptoms of a serious allergic reaction.

  • Breathing problems or wheezing
  • Racing heart
  • Fever or general ill feeling
  • Swollen lymph nodes
  • Swelling of the face, lips, mouth, tongue, or throat
  • Trouble swallowing or throat tightness
  • Itching, skin rash, or pale red bumps on the skin called hives
  • Nausea or vomiting
  • Dizziness, feeling lightheaded, or fainting
  • Stomach cramps
  • Joint pain

Blood Clots. Estradiol/norethindrone may cause a blood clot in your arteries or veins and could cause a stroke, heart attack, or venous thromboembolism (VTE), including a blood clot in the lungs (pulmonary embolism), in the back of your eye (retinal vein occlusion), or in your legs or arms (deep venous thrombosis). Stop using estradiol/norethindrone and get emergency help if you have any of the following signs of a blood clot.

  • Chest pain or pressure
  • Fast or abnormal heartbeat
  • Trouble breathing
  • Pain in your back, jaw, throat, or arm
  • Sweating, upset stomach, vomiting, or dizziness
  • Sudden weakness on one side of your body
  • Sudden and severe headache
  • Slurred speech or trouble understanding speech
  • Pain, swelling, or tenderness in your arm or leg
  • Vision loss
  • Bulging eyes
  • Double vision

Cancer. Estradiol/norethindrone can cause a new cancer to develop, such as  breast cancer, ovarian cancer, or endometrial cancer. Tell your health care provider about any new symptoms that you may get. Call your health care provider right away if you have any of the following symptoms.

  • New lump in your breast or armpit
  • Changes in the size, shape, texture, or temperature of your breast
  • Nipple changes
  • Unusual vaginal discharge
  • Belly or back pain
  • Need to pee more often or urgently
  • Unusual vaginal bleeding

Dementia. Estradiol/norethindrone may affect your brain, especially if you are 65 or older. Tell your health care provider right away if you or your friends or family notice that you have any of the following.

  • Memory problems, such as asking the same question over and over
  • Confusion or disorientation
  • Trouble with complex but familiar tasks, such as cooking a meal or paying your bills
  • Personality changes, such as depression, agitation, paranoia, and mood swings

Gallbladder Problems. Using estradiol/norethindrone can cause gallbladder problems, including cholecystitis and cholelithiasis (also known as gallstones). Call your health care provider right away if you have any of the following symptoms.

  • Your skin or the whites of your eyes turning yellowish in color (also called jaundice)
  • Fever
  • Pain in your upper stomach area
  • Stool (poop) that is clay-colored

Increased Blood Pressure (Hypertension). Estradiol/norethindrone may increase your blood pressure or make it worse if you have a history of high blood pressure. Call your health care provider if your blood pressure increases while taking this medicine.

If you measure your blood pressure and the top number (systolic) is 180 mm Hg or higher or the bottom number (diastolic) is 120 mm Hg or higher, get medical attention right away. Increases in blood pressure may not be noticeable, but look out for and tell your health care provider right away if you have any of the following symptoms of severely high blood pressure.

  • Sudden severe headache
  • Chest pain
  • Dizziness or confusion
  • Trouble breathing
  • Nausea or vomiting
  • Blurry or other changes to vision
  • Anxiety
  • Buzzing in the ears
  • Nosebleed
  • Feeling of skipped heartbeats

Fluid Retention (Edema). Estradiol/norethindrone can cause fluid retention, also called edema. Fluid retention can cause serious issues in people with certain conditions, such as heart failure or kidney problems. Call your health care provider right away if you have any of the following symptoms.

  • Chest pain
  • Irregular heartbeat
  • Shortness of breath
  • Stretched or shiny skin
  • Swollen body parts, such as the belly or ankles

Liver Damage. Liver damage, also called hepatotoxicity, can happen when using estradiol/norethindrone. Call your health care provider right away if you have any of the following symptoms of liver damage.

  • Nausea or vomiting
  • Stomach or belly pain
  • Fever
  • Weakness or unusual tiredness
  • Itching
  • Loss of appetite
  • Light-colored poop
  • Dark-colored urine (pee)
  • Your skin or the whites of your eyes turning yellowish in color (also called jaundice)

Uterine Fibroids. Estradiol/norethindrone may cause tumors (fibroids) in your uterus to get bigger. Some fibroids are small and cause no symptoms, while others may grow and cause problems. Talk to your health care provider if you have any of the following symptoms.

  • Heavy, long, painful periods
  • Pain in the lower belly or back
  • Painful sex
  • Peeing often 
  • Discomfort in the rectum

Warnings & Precautions

Who should not use estradiol/norethindrone?

Allergies to Ingredients. People who are allergic to any of the following should not use estradiol/norethindrone.

  • Estradiol
  • Norethindrone
  • Activella
  • Amabelz
  • CombiPatch
  • Lopreeza
  • Mimvey
  • Any of the ingredients in the specific product dispensed

Your pharmacist can tell you all of the ingredients in the specific estradiol/norethindrone products they stock.

Unusual Vaginal Bleeding. Estradiol/norethindrone should not be used if you have bleeding from the uterus or vagina that is not part of your menstrual cycle (period) or is unusual. 

Cancer. Estradiol/norethindrone should not be used if you have, suspect, or had breast cancer, or a cancer that is sensitive to estrogen. These conditions could worsen if you use estradiol/norethindrone.

Blood Clots. Estradiol/norethindrone should not be used if you have or had blood clots, including a blood clot in the lungs (pulmonary embolism) or deep venous thrombosis (DVT). In addition, the medicine should not be used if you have a condition that makes your blood more prone to getting blood clots (thrombophilia). Estradiol/norethindrone can increase the risk of developing a blood clot that could be dangerous, even life-threatening.

Heart Attack or Stroke. Estradiol/norethindrone should not be used if you have or had a stroke or heart attack. Estradiol/norethindrone can increase the risk of having a heart attack or stroke that could be dangerous, even life-threatening.

Liver Problems. Estradiol/norethindrone should not be used if your liver is not working as well as it should be. If there is a concern about the health of your liver, your health care provider may do tests to determine if it is working well enough to use this medicine.  

Pregnancy. Do not use estradiol/norethindrone if you are pregnant. If you become pregnant, contact your health care provider right away. See the Pregnancy section for more details.

What should I know about estradiol/norethindrone before using it?

Do not use estradiol/norethindrone unless it has been prescribed to you by a health care provider. Use it as prescribed.

Do not share estradiol/norethindrone with other people, even if they have the same condition as you. It may harm them.

Keep estradiol/norethindrone out of the reach of children. Since estradiol/norethindrone patches should be kept in a refrigerator, take special precautions to keep it away from children who also use the refrigerator.

If you use estradiol/norethindrone tablets, do not take a break in between packs. Since you will take one tablet daily, you will start the next pack of estradiol/norethindrone as soon as you finish the previous pack. 

If you use estradiol/norethindrone patches, allow the patch to reach room temperature before applying it to the skin. Apply one patch to the skin on the lower abdomen twice weekly. You will wear it for three to four days, then remove it and apply a new patch. Only wear one patch at a time. Consider using a calendar or app to help you remember when to change your patch.

Apply an estradiol/norethindrone patch to a smooth (fold free), clean, dry area on your lower abdomen. The area must be free of powder, oil, or lotion. Avoid places that will not be covered by your clothing, if you will be in the sun for long periods. Avoid the waistline, since clothing and belts may cause the patch to be rubbed off. Do not apply an estradiol/norethindrone patch near or on your breasts, birthmarks, tattoos, or areas that are injured, burned, irritated, or hairy. 

Apply an estradiol/norethindrone patch to a different area of your abdomen each time. Do not use the same application site two times in the same week.

It is okay to shower, bathe, or swim while using estradiol/norethindrone patches. If your patch falls off, reapply the same patch to another area of your lower abdomen. If the patch cannot be reapplied, use a new patch. 

When removing an estradiol/norethindrone patch, slowly peel the patch from the skin. Fold the patch in half, so that it sticks to itself and place it in the trash out of the reach of pets and children. Used patches still contain active medicine. 

If you notice any sticky residue on your skin after removing an estradiol/norethindrone patch, allow the area to dry for 15 minutes. Then, gently rub the area with an oil-based cream or lotion to remove the adhesive from your skin.

Make sure to keep all follow up appointments with your health care provider. They will use these appointments to check if your dose or medicine needs to be changed. Estrogen-containing medicines should be used at the lowest possible dose for only as long as they are needed.

Estradiol/norethindrone may cause some laboratory tests to give false readings, including thyroid function tests, certain hormone tests, and cholesterol blood work. Talk to your health care provider if you have any concerns.  

Perform monthly self-breast exams and have regular pelvic exams (female exam), breast exams (done by a health care provider), and mammograms (x-ray to look closely at breast tissue) before using estradiol/norethindrone and during treatment with it.

What should I tell my health care provider before using estradiol/norethindrone?

Tell your health care provider about all of your health conditions and any prescription or over-the-counter (OTC) medicines, vitamins/minerals, herbal products, and other supplements you are using. This will help them determine if estradiol/norethindrone is right for you.

In particular, make sure that you discuss any of the following.

Current and Past Health Conditions. Tell your health care provider if you have any of the following.

Tobacco Use. Smoking and tobacco use can increase your risk of getting heart disease, which increases your risk of having a heart attack, stroke, or blood clots. Tell your health care provider if you use any tobacco products before starting estradiol/norethindrone. 

Upcoming Surgery or Bed Rest. You may be at increased risk for some side effects of estradiol/norethindrone if you do not move around normally for an extended period of time. Tell your health care provider if you have any upcoming surgeries or need to be on bed rest. Your health care provider can tell you if or when you need to stop taking estradiol/norethindrone.

High Triglyceride Levels. If you have high triglyceride levels, estradiol/norethindrone may make your triglycerides even higher. Very high triglyceride levels can lead to inflammation of the pancreas, which is called pancreatitis. Tell your health care provider if you have high triglyceride levels.

Hysterectomy. Estradiol/norethindrone contains a progestin to decrease the chances of getting cancer of the uterus. Tell your health care provider if you have had a hysterectomy and do not have a uterus.

Other Medicines and Supplements. Estradiol/norethindrone may interact with other medicines and supplements. Before using estradiol/norethindrone, tell your health care provider about any prescription or over-the-counter (OTC) medicines, vitamins/minerals, herbal products, and other supplements you are using. See the Interactions section for more details.

Pregnancy. People who can become pregnant are not usually prescribed estradiol/norethindrone. Tell your health care provider if you are pregnant or plan to become pregnant. If you become pregnant while using estradiol/norethindrone, stop using the medicine right away and contact your health care provider.

Breastfeeding. Estradiol/norethindrone passes into breast milk. Tell your health care provider if you are breastfeeding or plan to breastfeed. Your health care provider will let you know if you should use estradiol/norethindrone while breastfeeding.

Interactions

Does estradiol/norethindrone interact with foods or drinks?

Eating grapefruit or drinking grapefruit juice while using estradiol/norethindrone increases levels of the medicine in your body and increases the risk for side effects. Talk to your health care provider if you eat grapefruit or drink grapefruit juice. 

It is unknown if drinking alcohol will affect estradiol/norethindrone.

Does estradiol/norethindrone interact with other medicines (drug interactions)?

Always tell your health care provider about any prescription or over-the-counter (OTC) medicines, vitamins/minerals, herbal products, and other supplements you are using.

In particular, make sure that you discuss if you are using any of the following before using  estradiol/norethindrone.

  • Carbamazepine (Carbatrol, Tegretol, and others), which is a medicine commonly used to treat seizures or nerve pain
  • Clarithromycin or erythromycin (Ery-Tab and others), which is a medicine used for bacterial infections
  • Ketoconazole or itraconazole (Sporanox, Tolsura), which is a medicine used for fungal infections
  • Phenytoin (Dilantin, Phenytek, and others), which is a medicine to control seizures
  • Rifampin (Rifadin), which is a medicine commonly used to treat an infection called tuberculosis
  • Rifabutin (Mycobutin), which is a medicine used to prevent Mycobacterium avium complex infection
  • St. John’s wort, which is a supplement that may be used for depression
  • A medicine for HIV or AIDS

Some other medicines may alter the blood levels of estradiol/norethindrone. Tell your health care provider about all medicines that you take or have recently taken.

This may not be a complete list of medicines that can interact with estradiol/norethindrone. Always check with your health care provider.

 

Does interact with other drugs you are taking?

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Overdose/Missed Dose

What should I do if I accidentally use too much estradiol/norethindrone?

If you or someone else has used too much estradiol/norethindrone, get medical help right away, call 911, or contact a Poison Control center at 800-222-1222.

What should I do if I miss a dose of estradiol/norethindrone?

If you miss a dose of estradiol/norethindrone tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and only take the next dose. Do not take double or extra doses.

An estradiol/norethindrone patch is left on the skin for three to four days in a row. If you forget to apply a new patch, remove the current patch and apply a new patch as soon as possible to a different area. Continue to follow the original dosing schedule. Do not use more than one patch at a time. 

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