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Drug Profile

The information on this site is intended to supplement and enhance, not replace, the advice of a physician who is familiar with your medical history. Decisions about your health should always be made ONLY after detailed conversation with your doctor.

Generic drug name: ethinyl estradiol with norethindrone (ETH in il es tra DYE ole with nor ETH in drone)
Brand name(s): ACTIVELLA, ALYACEN, AMABELZ, ARANELLE, COMBIPATCH, DASETTA, FEMHRT
GENERIC: available FAMILY: Hormone Combinations
Find the drug label by searching at DailyMed.

Limited Use [what does this mean?]
Generic drug name: conjugated estrogens with medroxyprogesterone (CON joo gay ted ESS troe jenz with me DROX ee proe)
Brand name(s): PREMPHASE, PREMPRO
GENERIC: not available FAMILY: Hormone Combinations
Find the drug label by searching at DailyMed.

Pregnancy and Breast-feeding Warnings [top]

PREGNANCY WARNING

Because of the potential for serious adverse effects to the fetus, these drugs should not be used by women with known or suspected pregnancy.

BREAST-FEEDING WARNING

Estrogens are excreted in breast milk and have caused adverse effects in nursing infants including jaundice and breast enlargement.  If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completly weaned her child.  These drugs may also decrease the amount and quality of breast milk. Because of the potential for adverse effects in nursing infants, you should not take these drugs while nursing.

Safety Warnings For This Drug [top]

FDA BLACK-BOX WARNING for conjugated estrogens with medroxyprogesterone (PREMPRO, PREMPHASE)

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA

Cardiovascular Disorders and Probable Dementia

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.

The estrogen-plus-progestin substudy of the Women's Health Initiative (WHI) reported increased risks of deep vein thrombosis (blood clots in large veins, most often in the legs), pulmonary embolism (blood clots in the lungs), stroke and heart attack in postmenopausal women (50 to 79 years of age) during 5.6 years of daily treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) per day relative to placebo.

The WHI's Memory Study (WHIMS), a substudy of WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during four years of daily treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Breast Cancer

The estrogen-plus-progestin substudy of the WHI also demonstrated an increased risk of invasive breast cancer.

In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens and medroxyprogesterone acetate.

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.

FDA BLACK-BOX WARNING
for ethinyl estradiol with norethindrone (FEMHRT)

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA

Cardiovascular Disorders and Probable Dementia

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.

The estrogen-plus-progestin substudy of the Women’s Health Initiative (WHI) reported increased risks of deep vein thrombosis (blood clots in large veins, most often in the legs), pulmonary embolism (blood clots in the lungs), stroke and heart attack in postmenopausal women (50 to 79 years of age) during 5.6 years of daily treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) per day relative to placebo.

The WHI’s Memory Study (WHIMS), a substudy of WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during four years of daily treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Breast Cancer

The estrogen-plus-progestin substudy of the WHI also demonstrated an increased risk of invasive breast cancer. In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens and medroxyprogesterone acetate.

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.

Beware of Compounding Pharmacists Selling "Bioidentical" Hormone Replacement Therapies, Claiming That They Are Safe

Pharmacy compound products are not approved by the FDA and their quality is questionable, as they are not produced in facilities meeting good manufacturing practice (GMP) guidelines.

Facts About This Drug [top]

These combination estrogen with progestin products are approved by the Food and Drug Administration (FDA) to manage the symptoms of menopause. These drugs also are approved to prevent osteoporosis. However, estrogens are no longer approved for the treatment of osteoporosis. Treatment solely for the prevention of postmenopausal osteoporosis should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.[1],[2]

...

These combination estrogen with progestin products are approved by the Food and Drug Administration (FDA) to manage the symptoms of menopause. These drugs also are approved to prevent osteoporosis. However, estrogens are no longer approved for the treatment of osteoporosis. Treatment solely for the prevention of postmenopausal osteoporosis should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.[1],[2]

The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake and, when needed, treatment with drugs.

Postmenopausal women require an average of 1,500 milligrams per day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 international units per day also may be required to ensure adequate daily intake in postmenopausal women.[1],[2]

The progestins medroxyprogesterone and norethindrone are added to the estrogen component of these products to reduce the risk of uterine cancer in women who have an intact uterus.

The Canadian Task Force on Preventive Health Care recommends "against the use of combined estrogen-progestin therapy and estrogen-only therapy for the primary prevention of chronic diseases in menopausal women." For the management of the symptoms of menopause, this Task Force recommends the following: "If the risks are acceptable to the woman and her physician, therapy of as short a duration a possible, and at as low a dose as possible, may be indicated."[3] We agree.

The North American Menopause Society (NAMS) has issued its position on the management of hot flashes in postmenopausal women. For mild hot flashes, lifestyle-related strategies such as keeping the core body temperature cool, participating in regular exercise and using paced respiration have shown some effectiveness without adverse effects.[4]

The NAMS found that, among nonprescription remedies, clinical trial results are insufficient to either support or refute the efficacy of soy foods and isoflavone supplements (soy or red clover), black cohosh or vitamin E for hot flashes. Single clinical trials have found no benefit for dong quai, evening primrose oil, ginseng, a Chinese herbal mixture, acupuncture or magnet therapy.[4]

Research published in 2005 in Obstetrics & Gynecology found that estrogen plus progestin therapy in postmenopausal women, known as hormone replacement therapy (HRT), increases the risk of urge and stress incontinence within four months of beginning treatment.

Because the risks of HRT outweigh its benefits for most uses, these products now have a black-box warning (see above) in their professional product labels. The FDA also has limited the approved uses of HRT to the short-term treatment of moderate-to-severe hot flashes associated with menopause. HRT is no longer approved for the long-term treatment of the symptoms of menopause. The FDA cautions prescribers that women with postmenopausal osteoporosis should use other products, such as alendronate (FOSAMAX), before resorting to HRT. In other words, HRT is the last choice for postmenopausal osteoporosis.[5]

Information from the Women’s Health Initiative trial showed that when postmenopausal women used a combination of estrogen and medroxyprogesterone hormone therapy, there was an increased risk of deep vein thrombosis (blood clots in large veins, most often in the legs), pulmonary embolism (blood clots in the lungs), stroke, heart attack, invasive breast cancer and probable dementia compared with women receiving a placebo.[6]

Another study published in JAMA reported that patients on hormone therapy were at an increased risk of ovarian cancer. [7]

The January 2014 issue of Worst Pills, Best Pills News reviewed the risks and benefits of HRT. Two major clinical trials published in 2002 and 2004 revealed a high incidence of breast cancer and stroke with long-term use of HRT. Although HRT use is now much lower than either before or after the 2002 study, the number of prescriptions for HRT remains troublingly high and may be increasing. HRT should therefore be used at the lowest dose and for the shortest duration necessary to meet treatment goals. To read more, see “Hormone Replacement Therapy: Use at the Lowest Dose for the Shortest Amount of Time.”

In 2019, Lancet published a study showing that the longer the use of all types of hormone therapy (except vaginal estrogen, such as estradiol vaginal cream [ESTRACE]), the higher the risk of invasive breast cancer (breast cancer that spreads into surrounding breast tissue). It also found that combination hormone therapy is associated with a higher breast cancer risk than estrogen-only therapy.[8]

In 2020, JAMA published an article warning that the use of combination estrogen and medroxyprogesterone increased the risk of breast cancer but made no difference in breast cancer death in women with a uterus compared with use of a placebo. Use of estrogen alone had a lower risk of breast cancer and breast cancer death in women who had a hysterectomy compared withuse of a placebo.[9]

Before You Use This Drug [top]

Do not use if you have or have had:

  • pregnancy or are breast-feeding
  • allergy to estrogens or progestins
  • abnormal or undiagnosed vaginal bleeding
  • severe liver disease, including liver tumors
  • high level of calcium in your blood
  • breast cancer
  • known or suspected cancer that is estrogen dependent
  • vein inflammation
  • blood-clotting disorder

Tell your doctor if you have or have had:

  • asthma
  • heart problems
  • epilepsy
  • high blood pressure
  • migraine headaches
  • severe kidney disease
  • diabetes
  • endometriosis
  • gallbladder or gallstone problems
  • liver disease
  • jaundice
  • porphyria
  • high cholesterol
  • pancreas disease
  • fibroids in uterus
  • blood-clotting disorder
  • inflammation of veins
  • stroke or circulatory brain disorder
  • clot in lungs
  • clot in eyes

When You Use This Drug [top]

  • See your doctor at least once a year.
  • Do breast self-exams.
  • Tell your doctor if you find any unusual breast lumps or discharge.
  • Menstrual bleeding may begin again, but with continuous therapy it will stop by 10 months.
  • Vaginal bleeding between menstrual periods will occur for the first three months after starting this drug; do not stop taking the drug. However, you should check with your doctor immediately if vaginal bleeding is unusual or continuous, if you miss a period, or you think you are pregnant.
  • If you are scheduled for any lab tests, tell your doctor that you are taking this drug.

How to Use This Drug [top]

  • Read the patient directions.
  • If you miss a dose, take it as soon as you remember, but skip it if it is almost time for the next dose. Do not take double doses.
  • Do not share your medication with others.
  • Take the drug at the same time(s) each day.
  • If taking combination therapy, take each drug at the right time.
  • For conjugated estrogens with medroxyprogesterone: Take with food if nausea occurs, especially for the first few weeks after starting this drug.
  • Store at room temperature with lid on tightly. Do not store in the bathroom. Do not expose to heat, moisture, or strong light. Keep out of reach of children.

Interactions with Other Drugs [top]

The following drugs, biologics (e.g., vaccines, therapeutic antibodies), or foods are listed in Evaluations of Drug Interactions 2003 as causing “highly clinically significant” or “clinically significant” interactions when used together with any of the drugs in this section. In some sections with multiple drugs, the interaction may have been reported for one but not all drugs in this section, but we include the interaction because the drugs in this section are similar to one another. We have also included potentially serious interactions listed in the drug’s FDA-approved professional package insert or in published medical journal articles. There may be other drugs, especially those in the families of drugs listed below, that also will react with this drug to cause severe adverse effects. Make sure to tell your doctor and pharmacist the drugs you are taking and tell them if you are taking any of these interacting drugs:

EVISTA, nelfinavir, NORVIR, raloxifene, ritonavir, VIRACEPT.

Adverse Effects [top]

Call your doctor immediately if you experience:

  • sudden loss of coordination (ethinyl estradiol with norethindrone acetate)
  • chest, leg, or groin pain (ethinyl estradiol with norethindrone acetate)
  • no menstrual period (conjugated estrogens with medroxyprogesterone)
  • breast pain or tenderness (ethinyl estradiol with norethindrone acetate)
  • high blood pressure (ethinyl estradiol with norethindrone acetate)
  • dizziness or lightheadedness (ethinyl estradiol with norethindrone acetate)
  • headache, severe and sudden (ethinyl estradiol with norethindrone acetate)
  • swelling of feet and lower legs (ethinyl estradiol with norethindrone acetate)
  • rapid weight gain (ethinyl estradiol with norethindrone acetate)
  • cough, fever, sneezing, or sore throat (ethinyl estradiol with norethindrone acetate)
  • change in menstrual period, including menstruating at the wrong time, change in amount of flow, breakthrough bleeding, or spotting (conjugated estrogens with medroxyprogesterone)
  • vaginal bleeding (ethinyl estradiol with norethindrone acetate)
  • pelvic pain or pressure (ethinyl estradiol with norethindrone acetate)
  • vaginal itching or irritation
  • thick, white vaginal discharge (conjugated estrogens with medroxyprogesterone)
  • change in vaginal discharge (ethinyl estradiol with norethindrone acetate)
  • nausea or vomiting (ethinyl estradiol with norethindrone acetate)
  • breast lumps
  • breast discharge
  • skin rash (conjugated estrogens with medroxyprogesterone)
  • yellow eyes or skin
  • stomach, side, or abdomen pain or tenderness
  • sudden shortness of breath (ethinyl estradiol with norethindrone acetate)
  • sudden slurred speech (ethinyl estradiol with norethindrone acetate)
  • sudden vision changes (ethinyl estradiol with norethindrone acetate)
  • weakness or numbness in arm or leg (ethinyl estradiol with norethindrone acetate)

Call your doctor if these symptoms continue:

  • abdominal pain or cramping (conjugated estrogens with medroxyprogesterone)
  • joint or back pain
  • flulike symptoms (ethinyl estradiol with norethindrone acetate)
  • breast enlargement, pain, or tenderness (conjugated estrogens with medroxyprogesterone)
  • diarrhea (conjugated estrogens with medroxyprogesterone)
  • dizziness
  • stomach discomfort following meals (conjugated estrogens with medroxyprogesterone)
  • painful menstrual periods (conjugated estrogens with medroxyprogesterone)
  • passing of gas
  • increase in amount of clear vaginal discharge (conjugated estrogens with medroxyprogesterone)
  • vaginal discharge (ethinyl estradiol with norethindrone acetate)
  • mental depression
  • nausea
  • itching
  • unusual tiredness
  • headaches
  • tense or aching muscles
  • increase in sexual desire (conjugated estrogens with medroxyprogesterone)
  • bloating or swelling of face, ankles, or feet (conjugated estrogens with medroxyprogesterone)
  • unusual weight gain or loss (conjugated estrogens with medroxyprogesterone)
  • mood changes or nervousness (conjugated estrogens with medroxyprogesterone)
  • trouble sleeping
  • vomiting (conjugated estrogens with medroxyprogesterone)

Signs of overdose (ethinyl estradiol with norethindrone acetate):

  • nausea or vomiting
  • having a menstrual period

If you suspect an overdose, call this number to contact your poison control center: (800) 222-1222.

Periodic Tests[top]

Ask your doctor which of these tests should be done periodically while you are taking this drug:

  • blood pressure measurements
  • physical exam
  • breast exam or mammogram
  • evaluation of endometrium (mucous membrane lining the uterus)
  • liver function tests
  • cholesterol levels
  • Pap test

last reviewed April 30, 2021