Pronunciation:

es-tra-DYE-ol, nor-ETH-in-drone AS-e-tate

Brand Names:

• Combipatch
• Estalis
• Estalis-Sequi

Dosage Forms:

• Patch, Extended Release

Warnings:

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. An increased risk of DVT, pulmonary embolism, stroke, myocardial infarction, and invasive breast cancer have been reported. An increased risk of probable dementia in postmenopausal women 65 years of age or older has also been reported. There is an increased risk of endometrial cancer in women with a uterus who use unopposed estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman .

Classifications:

Therapeutic—

Estrogen/Progestin Combination

Pharmacologic—

Estrogen

Uses of This Medicine:

Estradiol and norethindrone skin patch is used to treat moderate to severe hot flashes and other symptoms of menopause. It is also used to treat changes in and around the vagina (such as vaginal dryness, itching, and burning) caused by low estrogen levels or menopause. This medicine is also used to treat certain conditions in women before menopause if their ovaries do not make enough estrogens naturally.

This medicine is a combination of two hormones: an estrogen hormone (estradiol) and a progestin hormone (norethindrone). These hormones are absorbed through your skin into your body. It works by preventing symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (hot flashes) in women during menopause.

This medicine is available only with your doctor's prescription.

Before Using This Medicine:

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies—

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children—

Use of CombiPatch® is not indicated in children.

Older adults—

Although appropriate studies on the relationship of age to the effects of CombiPatch® have not been performed in the geriatric population, no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have breast cancer, strokes, or dementia, which may require caution in patients receiving this medicine.

Breast-feeding—

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Other medicines—

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Tranexamic Acid

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abametapir
• Amifampridine
• Amobarbital
• Amoxicillin
• Ampicillin
• Amprenavir
• Apalutamide
• Aprepitant
• Armodafinil
• Artemether
• Bacampicillin
• Belzutifan
• Betamethasone
• Bexarotene
• Boceprevir
• Bosentan
• Bupropion
• Butabarbital
• Butalbital
• Carbamazepine
• Carbenicillin
• Cefaclor
• Cefadroxil
• Cefdinir
• Cefditoren
• Cefixime
• Cefpodoxime
• Cefprozil
• Ceftazidime
• Ceftibuten
• Cefuroxime
• Cenobamate
• Ceritinib
• Clobazam
• Cloxacillin
• Colesevelam
• Conivaptan
• Cyclacillin
• Cyclosporine
• Dabrafenib
• Darunavir
• Dexamethasone
• Dicloxacillin
• Dipyrone
• Donepezil
• Doxycycline
• Efavirenz
• Elagolix
• Elvitegravir
• Encorafenib
• Enzalutamide
• Eslicarbazepine Acetate
• Etravirine
• Fedratinib
• Felbamate
• Fexinidazole
• Fosamprenavir
• Fosaprepitant
• Fosnetupitant
• Fosphenytoin
• Grazoprevir
• Griseofulvin
• Guar Gum
• Indinavir
• Isotretinoin
• Itraconazole
• Ivosidenib
• Lesinurad
• Lixisenatide
• Lopinavir
• Lorlatinib
• Lumacaftor
• Mavacamten
• Mephobarbital
• Methohexital
• Minocycline
• Mitapivat
• Mitotane
• Mobocertinib
• Modafinil
• Mycophenolate Mofetil
• Mycophenolic Acid
• Nafcillin
• Nelfinavir
• Netupitant
• Nevirapine
• Octreotide
• Oxacillin
• Oxcarbazepine
• Oxytetracycline
• Penicillin G
• Penicillin G Procaine
• Penicillin V
• Pentobarbital
• Phenobarbital
• Phenylbutazone
• Phenytoin
• Pitolisant
• Pixantrone
• Prednisolone
• Prednisone
• Primidone
• Red Clover
• Rifabutin
• Rifampin
• Rifapentine
• Rilpivirine
• Ritonavir
• Rufinamide
• Saquinavir
• Secobarbital
• Simeprevir
• Somatrogon-ghla
• St John's Wort
• Sugammadex
• Sultamicillin
• Tazemetostat
• Telaprevir
• Telotristat Ethyl
• Tetracycline
• Theophylline
• Thiopental
• Thioridazine
• Ticarcillin
• Tigecycline
• Tipranavir
• Tirzepatide
• Tizanidine
• Topiramate
• Troglitazone
• Ulipristal
• Valproic Acid
• Voxilaprevir

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amitriptyline
• Atazanavir
• Atorvastatin
• Clomipramine
• Diazepam
• Doxepin
• Ginseng
• Imipramine
• Lamotrigine
• Levothyroxine
• Licorice
• Lorazepam
• Parecoxib
• Selegiline
• Tacrine
• Temazepam
• Tipranavir
• Triazolam
• Troleandomycin
• Valdecoxib
• Voriconazole
• Warfarin

Other interactions—

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Caffeine

Other medical problems—

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal or unusual vaginal bleeding or
• Blood clots (eg, deep vein thrombosis, pulmonary embolism), active or history of or
• Breast cancer, known or suspected, or a history of or
• Heart attack, history of or
• Liver disease or
• Protein C, protein S, or other known blood clotting disorders or
• Stroke, history of or
• Tumors (estrogen-dependent), known or suspected—Should not be used in patients with these conditions.

• Asthma or
• Bone problems or
• Diabetes or
• Edema (fluid retention or body swelling) or
• Endometriosis or
• Epilepsy (seizures) or
• Gallbladder disease or
• Hereditary angioedema (swelling of the face, lips, tongue, or throat) or
• Hypercalcemia (high calcium in the blood) or
• Hypocalcemia (low calcium in the blood) or
• Hypothyroidism (an underactive thyroid) or
• Jaundice during pregnancy or from using hormonal therapy in the past or
• Liver tumors or
• Migraine headache or
• Porphyria (an enzyme problem) or
• Systemic lupus erythematosus (SLE)—Use with caution. May make these conditions worse.

• Heart disease or
• Hypercholesterolemia (high cholesterol or fats in the blood) or
• Hypertension (high blood pressure) or
• Hypertriglyceridemia (high triglycerides or fats in the blood) or
• Obesity, or history of or
• Prolonged periods of immobilization—Use with caution. These conditions may increase risk for more serious side effects.

Proper Use of This Medicine:

It is very important that you use this medicine exactly as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects.

This medicine comes with a patient information leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Before starting CombiPatch® therapy, you may need to tell your doctor if you are currently using continuous estrogen or combination estrogen plus progestin therapy. This will allow your doctor to determine when to start your treatment.

You may have monthly bleeding or spotting at the completion of each cycle.

This transdermal patch system is to be applied on the skin of the lower abdomen (lower stomach area) two times a week, depending on your dosing regimen (either continuous combined regimen or continuous sequential regimen), as advised by your doctor.

To use the skin patch:

• Wash your hands with soap and water before and after you use this medicine.
• Carefully tear open the pouch when you are ready to put the patch on your skin. Do not cut it.
• Peel off the backing from the patch and apply the patch to a clean, dry, and hair-free area of the lower stomach. This area must be free of powder, oil, or lotion for the patch to stick on to your skin.
• Press the patch firmly in place with your hand for about 10 seconds.
• Do not apply the patch on the breast or over any skin folds. Do not apply the patch on oily, broken, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos). Avoid applying the patch on the waistline or other places where tight clothing may rub it off.
• Wear the patch at all times until it is time to put on a new patch. Do not expose it to the sun for long periods of time.
• When replacing your patch, make sure to apply the new patch to a different area of your lower abdomen. Wait at least 1 week before applying a patch to the same area.
• When changing a patch, slowly peel it off from your skin. If you have any patch adhesive left on your skin, allow it to dry for 15 minutes and gently rub the sticky area with oil or lotion to remove it. It is best to change your patch on the same days of each week to help you remember.
• You may take a bath, shower, or swim while using this medicine. Doing so will not affect the patch.
• If a patch falls off, just put it back on a different area. If the patch does not stick completely, put on a new patch but continue to follow your original schedule for changing your patch.
• To throw away a used patch: Fold the patch in half with the sticky side together and place it in a sturdy child-proof container. Throw this container in the trash away from children and pets. Do not flush the patch down the toilet.

Dosing—

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For transdermal dosage form (patch):
  • For treatment of hot flashes, atrophic vaginitis caused by menopause:
    • Continuous combined regimen:
      • Adults—Apply 1 CombiPatch® two times a week (every 3 to 4 days) for a 28-day cycle. One CombiPatch® contains 0.05 milligrams (mg) of estradiol and 0.14 or 0.25 mg of norethindrone).
      • Children—Use is not recommended.
    • Continuous sequential regimen:
      • Adults—Apply 0.05 milligram (mg) estradiol patch (Vivelle-Dot®) two times a week (every 3 to 4 days) for the first 14 days of the 28-day cycle. Then, apply one CombiPatch® two times a week (every 3 to 4 days) for the next 14 days of the 28-day cycle. One CombiPatch® contains 0.05 milligrams (mg) of estradiol and 0.14 or 0.25 mg of norethindrone).
      • Children—Use is not recommended.

Missed dose—

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.

Storage—

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the patches at room temperature in a closed container, away from heat, moisture, and direct light.

Store the unopened pouches at room temperature for up to 6 months. Do not store the patch outside of its pouch.

Precautions While Using This Medicine:

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and does not cause unwanted effects. Pelvic exam, breast exam, and mammogram (breast x-ray) may be needed to check for unwanted effects, unless your doctor tells you otherwise. Be sure to keep all appointments.

It is unlikely that a postmenopausal woman may become pregnant. But, you should know that using this medicine while you are pregnant could harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away.

Using this medicine may increase your risk for having blood clots, strokes, or heart attacks. This risk may continue even after you stop using the medicine. Your risk for these serious problems is even greater if you have high blood pressure, high cholesterol in your blood, diabetes or are overweight or smoke cigarettes. Contact your doctor immediately if you experience chest pain, confusion, difficulty speaking, double vision, headaches, an inability to move arms, legs or facial muscle, or an inability to speak.

Using this medicine may increase your risk of endometrial cancer, breast cancer, or uterine cancer. Talk with your doctor about this risk. Check with your doctor immediately if your experience abnormal vaginal bleeding.

Do not use this medicine if you have had your uterus (womb) removed (hysterectomy).

Using this medicine may increase your risk of dementia, especially in women 65 years of age and older.

Check with your doctor immediately if severe headache or sudden loss of vision or any other change in vision occurs while you are using this medicine. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

This medicine may cause serious types of allergic reactions, including anaphylaxis which can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, lightheadedness or dizziness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth with this medicine.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine before you have surgery or if you need to stay in bed for an extended time. This medicine may affect the results of certain medical tests.

Do not eat grapefruit or drink grapefruit juice while you are using this medicine. Grapefruit and grapefruit juice may change the amount of this medicine that is absorbed in the body.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

Side Effects of This Medicine:

Along with its needed effects, a medicine 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:

More common

Bloating or swelling of the face, arms, hands, lower legs, or feet

heavy non-menstrual vaginal bleeding

itching of the vagina or genital area

pain during sexual intercourse

rapid weight gain

thick, white vaginal discharge with no odor or with a mild odor

tingling of the hands or feet

unusual weight gain or loss

Less common

Cough or hoarseness

fever or chills

lower back or side pain

painful or difficult urination

Incidence not known

Abdominal or stomach bloating or fullness

abdominal or stomach pain

blurred vision

change in vaginal discharge

clay-colored stools

clear or bloody discharge from the nipple

dark urine

diarrhea

dimpling of the breast skin

dizziness

gaseous abdominal or stomach pain

headache, severe and throbbing

hives

hoarseness

inverted nipple

irritation

itching

joint pain, stiffness or swelling

large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs

loss of appetite

lump in the breast or under the arm

nausea and vomiting

nervousness

pain or feeling of pressure in the pelvis

persistent crusting or scaling of the nipple

pounding in the ears

rash

recurrent fever

redness of the skin

redness or swelling of the breast

severe cramping of the uterus

slow or fast heartbeat

sore on the skin of the breast that does not heal

swelling of the eyelids, face, lips, hands, or feet

tightness in the chest

troubled breathing or swallowing

unpleasant breath odor

unusual tiredness or weakness

vaginal bleeding

vomiting of blood

yellow eyes or skin

Some side effects 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

Acid or sour stomach

back pain

belching

body aches or pain

breast pain

burning, itching, redness, skin rash, swelling, or soreness at the application site

congestion

cramps

difficulty with moving

discouragement

dryness or soreness of the throat

excess air or gas in the stomach or intestines

feeling sad or empty

general feeling of discomfort or illness

headache

heartburn

heavy bleeding

increased clear or white vaginal discharge

indigestion

irritability

lack or loss of strength

loss of interest or pleasure

muscle aches and pains

muscle stiffness

pain during sexual intercourse

pain or tenderness around the eyes and cheekbones

passing gas

shivering

sneezing

stomach discomfort or upset

stuffy or runny nose

sweating

tender, swollen glands in the neck

thick, white vaginal discharge with no odor or with a mild odor

tiredness

trouble concentrating

trouble sleeping

Less common

Blemishes on the skin

difficulty having a bowel movement (stool)

longer or heavier menstrual periods

pimples

Incidence not known

Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings

change in color of the treated skin

decreased interest in sexual intercourse

dizziness or lightheadedness

dull ache or feeling of pressure or heaviness in the legs

feeling of constant movement of self or surroundings

inability to have or keep an erection

increased in sexual ability, desire, drive, or performance

increased interest in sexual intercourse

itching skin near damaged veins

loss in sexual ability, desire, drive, or performance

sensation of spinning

weight gain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.