Estalis (Estradiol/Norethindrone) Patch 140/50ug

Estrogen and Progestin Combination

“ALERT: US Boxed Warning

Endometrial cancer:

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

Cardiovascular disease:

Estrogen-alone therapy should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg) alone, relative to placebo.

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.

Breast cancer:

The Women’s Health Initiative (WHI) estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

Dementia:

Estrogen-alone therapy should not be used for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years and older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Estrogen plus progestin therapy should not be used for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years or older during 4 years of treatment with daily 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.

Risk vs benefit:

In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). 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.”

Brand Name Canada: Estalis
US Equivalent: CombiPatch

CSA NA – FDA Approved – REMS (N) – Can Ship

Estrogen is a female sex hormone that supports the development and function of the female reproductive system, secondary sex characteristics and urogenital structures.  Estradiol is the principle female estrogen and inhibits the pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) thereby inhibiting ovulation through a negative feedback system.  

Norethindrone is a progestin is a synthetic form of progesterone which is another female reproductive hormone.  Progestin inhibits gonadotropin production which will prevent follicular maturation and subsequently ovulation.  Progestin also reduces the risk of endometrial hyperplasia as it thins out the endometrial lining of the uterus.

Estradiol+Norethindrone is officially indicated for hypoestrogenism, vasomotor symptoms associated with menopause, vulvar and vaginal atrophy associated with menopause and osteoporosis prevention.

Do not use in women with an increased risk of invasive breast cancer

Do not use in women to prevent or treat dementia

Do not use unopposed estrogen in women with a uterus

Do not use in women with endometriosis

Use with caution in women with pre-existing hypertriglyceridemia

Use with caution in women with ovarian cancer

Use with caution in women with retinal vascular thrombosis

Use with caution in asthma, carbohydrate intolerance, cardiovascular disease, fluid retention, hepatic dysfunction, hypoparathyroidism, migraines, porphyria, and system lupus erythematosus

Hypoestrogenism

CombiPatch: Apply one patch twice weekly.

CombiPatch: Apply estradiol only patch for the first 14 days of the cycle, followed by one patch twice weekly for the next 14 days.

Vasomotor Symptoms Associated with Menopause

Activella, Activelle, Activelle LD, Lopreeza, Mimvey: Take one tablet daily.

CombiPatch: Apply one patch twice weekly.

CombiPatch: Apply estradiol only patch for the first 14 days of the cycle, followed by one patch twice weekly for the next 14 days.

Estalis: Apply one patch twice weekly.

Vulvar and Vaginal Atrophy Associated with Menopause

Activella, Activelle, Amabelz, Lopreeza, Mimvey: Take 1 tablet once daily.

CombiPatch: Apply one patch twice weekly.

CombiPatch: Apply estradiol only patch for the first 14 days of the cycle, followed by one patch twice weekly for the next 14 days.

Estalis: Apply one patch twice weekly.

Osteoporosis Prevention

Activella, Activelle, Activelle LD, Lopreeza, Mimvey: Take one tablet once daily.

*When treating symptoms of vulvar and vaginal atrophy, topical application should be considered.

How Do You Take the Tablet: You can take tablets with food or after a meal to reduce nausea.   Take the medication exactly as prescribed by your doctor.  If you miss a dose, make sure to take it as soon as possible.  However, if it is almost time for your next dose, skip the missed dose and continue with your regular schedule.

How Do You Use the Patch: Apply the patch to clean dry skin to either the lower abdomen or buttocks.  Rotate the application sites, allowing at least a one-week interval before applying to the same skin site.  If the patch falls off, you can reapply to another area of the lower abdomen or buttocks.  Women, who are not on any concurrent estrogen/progestin therapy can start using the patch anytime.  However, if women are on concurrent estrogen/progestin therapy then complete the current cycle prior to starting the patch.  

Contact Your Doctor if You Ever Experience:  If you experience a sudden, intense, severe headache or chest pain; sudden loss of coordination; sudden loss of vision or speech disturbances; chest or calf pain; weakness in the extremities; sudden shortness of breath of pain with breathing (may indicate thromboembolic disorder); persistent or recurrent vaginal bleeding (may indicate endometrial cancer); edema; abdominal pain or jaundice (may indicate hepatitis or gallbladder disease).

The frequency of side effects is not well defined and some of the adverse reactions are dependent on the dosage form and combination therapy used:

>10%

Central Nervous System: Headache (23%)

Gastrointestinal: Abdominal pain (12%)

Genitourinary: Mastalgia (16%)

Neuromuscular and Skeletal: Back pain (12%)

Respiratory: Upper respiratory tract infection (21%), flu-like symptoms (11%)

Hormone Replacement Therapy

Hormone Replacement Therapy (HRT) refers to the use of an estrogen and a progestin in post-menopausal women.  In estrogen replacement therapy (ERT) only estrogen is administered.  It is critically important to include a progestin to reduce an estrogen induced risk of endometrial hyperplasia in women.  Estrogen replacement therapy is only used in women who have had a hysterectomy and thus are not at risk for these problems.

Treatment of Menopausal Symptoms

HRT effectively relieves or eliminates vasomotor symptoms (hot flushes, sweating), sleep disturbance and poor concentration in a dose-dependent manner. 

Treatment of Urogenital Problems

HRT effectively treats post-menopausal vaginal dryness and dyspareunia with vaginal therapy being most effective.  Furthermore, there is evidence supporting the usage of vaginal estrogens in reducing the frequency of post-menopausal urinary tract infections.

Prevention and Treatment of Osteoporosis 

HRT (with or without a progestin) taken for a period of at least 5 to 10 years is estimated to reduce the risk of osteoporosis-related hip fractures by at least 25%, wrist fractures by 25% to 75% and vertebral fractures by at least 50%; the reduction in risk is directly related to the duration of use.  For optimal protection against fracture, HRT should be started within 3 to 5 years after the last menstrual period.  

Other Uses: There is limited evidence that HRT may help minimize weight gain, prevent skin wrinkling and dryness which typically occur following menopause.

Place in Therapy

Current clinical research suggests that HRT should not be used routinely and/or long-term in post-menopausal women.  Those women who are likely to experience benefits from HRT should fully understand the fully the benefits along with the risks associated with HRT and agree to regular medical examinations. Only short-term therapy is recommended due to the risks of breast cancer, thromboembolism, and coronary heart disease.

Benefits Versus Risks Associated with HRT

Common Problems and Suggestions

General Dosage Considerations

Progestin must be included in HRT for women with an intact uterus to reduce the estrogenic-induced risk of endometrial hyperplasia and carcinoma.  A progestin is not needed if a woman has had a hysterectomy.  The progestin dosage depends on the estrogen dose.

Estrogen doses required to treat menopausal vasomotor symptoms should be titrated to individual response.  Younger women have been shown to need higher doses.  It is encouraged that women discontinue every three to six months to determine if estrogen is still needed.

Estrogen Dosing Considerations:

To Preserve Bone Mineralization and Prevent Bone Thinning

Oral Conjugated Estrogen: 0.625mg daily.

Oral Estradiol-17β: 1-2mg daily.

Estradiol-16β Transdermal Patch: 50mcg daily.

Continuous Estrogen Plus Progestin (Continuous Combined Regimen)

This regimen provides relief from menopausal symptoms while avoiding withdrawal bleeding.  It is designed to induce amenorrhea, however spotting can in the first 6 to 12 months on regimens of conjugated estrogens plus progestins.  Most women develop amenorrhea within 12 months.

1. Oral conjugated estrogen 0.3mg to 1.25mg daily plus oral medroxyprogesterone 2.5mg to 5mg or micronized progesterone 100mg daily.
2. Ethinyl estradiol 5mcg plus norethindrone 1mg daily.

Continuous Estrogen Plus Cyclic Progestin
This regimen provides relief from menopausal symptoms with regular withdrawal bleeding.  It may be tolerated than continuous progestin during the first year of menopause.

1. Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) plus oral medroxyprogesterone 5mg to 10mg daily or micronized progesterone 200mg daily for 12-14 days per months.
2. Transdermal estradiol 50mcg daily for 2 weeks then combined with norethindrone 250mcg for 2 weeks.
3. Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) continuously with medroxyprogesterone 10mg daily for 14 days every 3 months.  With this regimen, withdrawal bleeding occurs only once every 3 months, however a minor percentage of women may have spotting and withdrawal bleeding.

Cyclic Estrogen

Menopausal vasomotor symptoms may return during estrogen-free days.

1. Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) for 21 to 25 days each month with medroxyprogesterone 10mg daily for the last 12-14 days of every month.

Progestin Only

Used if estrogen is contraindicated.

1. Oral medroxyprogesterone 10mg to 20mg daily on response.

Vaginal Preparations

Vaginal preparations in the form of creams, gels, ovules only treat urogenital symptoms.  Vaginal preparations can be applied daily until symptoms resolve and can be used as a maintenance therapy with creams/gels/ovules being used twice weekly or a vaginal ring. 

Available Dosage Forms