What Is Estradiol/Norethindrone?

Estradiol/Norethindrone is a combination hormone replacement therapy (HRT) containing an estrogen (estradiol) and a progestin (norethindrone acetate). It is FDA-approved for the treatment of moderate-to-severe vasomotor symptoms (hot flashes) associated with menopause, moderate-to-severe vulvar and vaginal atrophy, and the prevention of postmenopausal osteoporosis.

It is available as oral tablets under brand names such as Activella, Amabelz, Lopreeza, and Mimvey, as well as a transdermal patch sold as CombiPatch. Generic versions are widely available for the oral formulations.

How Does It Work?

Estradiol is a synthetic form of estrogen that replaces declining estrogen levels in postmenopausal women, relieving vasomotor symptoms like hot flashes and night sweats, and preventing bone loss that can lead to osteoporosis.

Norethindrone acetate is a progestin added to protect the uterine lining (endometrium) from the overgrowth that unopposed estrogen can cause. This combination reduces the risk of endometrial hyperplasia and endometrial cancer in women who still have a uterus.

The oral tablet is taken once daily, while the transdermal patch is applied twice weekly to deliver a steady dose of both hormones through the skin.

What Doses Are Available?

• Oral tablet: 1 mg estradiol / 0.5 mg norethindrone acetate
• Oral tablet: 0.5 mg estradiol / 0.1 mg norethindrone acetate
• Transdermal patch (CombiPatch): 0.05 mg/day estradiol / 0.14 mg/day norethindrone acetate
• Transdermal patch (CombiPatch): 0.05 mg/day estradiol / 0.25 mg/day norethindrone acetate

How Hard Is It to Find Estradiol/Norethindrone in Stock?

Estradiol/Norethindrone has a findability score of 55 out of 100, meaning it can be intermittently difficult to find in stock. The oral tablet formulations (generic Activella, Amabelz, Lopreeza, Mimvey) are generally available at most pharmacies, but the transdermal patch (CombiPatch) has experienced significant shortages tracked by ASHP.

Broader estrogen patch shortages in 2024–2025 were driven by increased prescribing after updated FDA guidance on hormone replacement therapy safety, combined with limited manufacturing capacity for transdermal systems. If your pharmacy is out of stock, try using Medfinder to locate nearby pharmacies that have it available, or ask your prescriber about switching between oral and patch formulations.

Who Prescribes It?

Estradiol/Norethindrone is commonly prescribed by:

• Obstetricians and Gynecologists (OB/GYN) — the most common prescribers for menopausal hormone therapy
• Endocrinologists — for complex hormonal management
• Primary Care and Family Medicine physicians — for routine menopause symptom management
• Internal Medicine doctors — especially for osteoporosis prevention
• Menopause specialists — certified by the Menopause Society (formerly NAMS)

Telehealth prescribing is also available for this medication through various online hormone therapy clinics.

Is It a Controlled Substance?

No. Estradiol/Norethindrone is not a controlled substance and has no DEA scheduling. It is available by prescription only but does not carry the additional restrictions associated with controlled medications.

Side Effects

Common side effects of Estradiol/Norethindrone include:

• Headache
• Breast pain or tenderness
• Nausea
• Bloating and abdominal cramps
• Back pain
• Vaginal bleeding or spotting
• Weight changes
• Mood changes
• Hair loss

Serious side effects (seek medical attention immediately):

• Blood clots (deep vein thrombosis, pulmonary embolism)
• Stroke or heart attack
• Signs of breast cancer
• Severe allergic reactions
• Vision changes
• Liver problems (jaundice, dark urine)

Boxed Warning: Estrogen plus progestin therapy carries increased risks of cardiovascular disorders, breast cancer, and probable dementia in women 65 and older. Use the lowest effective dose for the shortest duration needed.

Alternatives

If you cannot find Estradiol/Norethindrone or it is not right for you, the following alternatives may be discussed with your doctor:

• Prempro (Conjugated Estrogens/Medroxyprogesterone Acetate) — another combined estrogen/progestin oral tablet for menopausal symptoms and osteoporosis prevention
• Climara Pro (Estradiol/Levonorgestrel Transdermal Patch) — a combination estrogen/progestin patch applied once weekly
• Bijuva (Estradiol/Progesterone Capsules) — a combination of estradiol and bioidentical progesterone in an oral capsule
• Premphase (Conjugated Estrogens/Medroxyprogesterone) — a sequential estrogen/progestin regimen for menopause management

Drug Interactions

Estradiol/Norethindrone can interact with several medications:

• CYP3A4 inducers (rifampin, carbamazepine, phenobarbital, phenytoin, St. John's Wort) — may decrease hormone levels, reducing effectiveness
• CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, ritonavir) — may increase hormone levels and side effects
• Thyroid replacement therapy — estrogen may increase thyroid-binding globulin, potentially requiring higher thyroid medication doses
• Anticoagulants (warfarin) — estrogen may affect coagulation; INR monitoring is recommended
• Lamotrigine — estrogen/progestin combinations may decrease lamotrigine levels
• Diabetes medications — estrogen may affect glucose tolerance, requiring dose adjustments

Food interactions: Grapefruit juice may increase estrogen levels. Alcohol may significantly increase circulating estradiol. Avoid St. John's Wort as it may reduce effectiveness.

Final Thoughts

Estradiol/Norethindrone is a well-established combination hormone replacement therapy that helps millions of postmenopausal women manage hot flashes, vaginal atrophy, and osteoporosis risk. While the oral generic tablets are generally available, the CombiPatch transdermal formulation has experienced shortages due to increased demand and limited manufacturing capacity.

If you're having trouble finding Estradiol/Norethindrone in stock at your pharmacy, use Medfinder to search nearby pharmacies for real-time availability. Generic oral tablets offer significant savings at $15 to $50 per month with discount cards. Always discuss formulation changes with your prescriber, and use the lowest effective dose for the shortest duration consistent with your treatment goals.