Estradiol / Norethindrone Acetate (Estalis)

1. Health Canada Product Monograph — Estradiol / Norethindrone Acetate

• Estalis is used to relieve moderate to severe menopausal symptoms, such as hot flushes, sleep disturbances, and vaginal or vulvar dryness, caused by naturally occurring or surgically induced low estrogen levels.
• Estalis is intended only for women who still have their uterus, since the norethindrone acetate component protects the uterine lining from overgrowth caused by unopposed estrogen.
• Estalis should be prescribed at the lowest effective dose and for the shortest duration consistent with the patient's treatment goals, since it is not approved for preventing heart disease.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Estalis must not be used during pregnancy.
• Both the estrogen and progestin components can cause harm to a developing fetus.
• Estalis is contraindicated in patients with known or suspected pregnancy.

• Estalis must not be used while breastfeeding.
• Estalis is contraindicated in breastfeeding patients.

• No clinical studies evaluated the effect of Estalis in women over 65 years of age, so Estalis is not recommended for women in this age group.
• Combined estrogen-progestin hormone therapy in women 65 years of age and older has been associated with an increased risk of probable dementia.

• Estalis is not indicated for use in children.

• Estalis is available in two strengths: 140 mcg norethindrone acetate with 50 mcg estradiol per day, and 250 mcg norethindrone acetate with 50 mcg estradiol per day.
• A new patch is applied twice weekly on a continuous basis, worn on the abdomen or buttocks, as part of an uninterrupted 28-day treatment cycle.
• Women who are not currently on oral estrogen can start Estalis right away; women switching from oral estrogen should start Estalis once menopausal symptoms reappear after stopping the oral therapy.
• The site chosen for each new patch should be rotated, avoiding the same skin area for at least one week, and the patch must not be applied to the breasts.
• If irregular uterine bleeding persists after uterine causes have been ruled out, switching from the continuous combined regimen to a sequential regimen may be more appropriate.
• No studies have been conducted in patients with kidney or liver impairment; Estalis is contraindicated in patients with severe liver impairment.
• The need for continued treatment should be reassessed periodically, and attempts to taper or stop the medication should be made every 3 to 6 months.
• If a patch falls off, it can be reapplied, or a new patch can be applied if it will not stick again; either way, the original twice-weekly schedule should continue unchanged.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Overdose with estrogen products has not been reported to cause serious acute harm, even in cases of large accidental ingestion by young children, though it may cause nausea, breast discomfort, fluid retention, bloating, or vaginal bleeding in women.
• Overdose of the norethindrone acetate (progestin) component has been associated with low mood, tiredness, acne, and excess body or facial hair growth.
• Because Estalis is delivered through the skin, removing the patch rapidly lowers blood levels of both estradiol and norethindrone acetate, which is the primary treatment for a suspected overdose.
• Treatment of overdose beyond patch removal is symptomatic and supportive, based on the specific symptoms present.

• Redness, itching, burning, or irritation at the patch application site is the most commonly reported side effect.
• Headache may occur, and is very common.
• Dizziness may occur.
• Breast pain or tenderness may occur, and is very common.
• Breast enlargement may occur.
• Menstrual-type symptoms, including painful periods (dysmenorrhea) and menstrual irregularities, are very common.
• Irregular vaginal bleeding or spotting may occur, particularly in the first 6 months of continuous treatment.
• Nausea may occur.
• Abdominal bloating, pain, or indigestion may occur.
• Diarrhea may occur.
• Acne or dry skin may occur.
• Rash or itching (pruritus) of the skin may occur.
• Back pain, pain in the arms or legs, or general aches may occur.
• Weight gain may occur.
• Fluid retention (peripheral edema) may occur.
• Fatigue (asthenia) may occur.
• Mood changes, including depression, nervousness, or irritability, may occur.
• Insomnia may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Combined estrogen-progestin therapy increases the risk of invasive breast cancer with use beyond short-term treatment.
• Combined estrogen-progestin therapy increases the risk of heart attack, stroke, and blood clots, including deep vein thrombosis and pulmonary embolism.
• Combined estrogen-progestin therapy in women 65 and older increases the risk of probable dementia.
• Combined estrogen-progestin therapy has been associated with an increased risk of ovarian cancer with five or more years of use.
• Unopposed or inadequately balanced estrogen exposure can lead to overgrowth of the uterine lining (endometrial hyperplasia) or, rarely, endometrial cancer.
• Benign liver tumors (hepatic adenomas) have been associated with combined hormone products and can rarely rupture, causing life-threatening internal bleeding.
• Gallbladder disease requiring surgery occurs more often in women using postmenopausal estrogen.
• Severe anaphylactic or anaphylactoid allergic reactions have been reported, involving hives, swelling of the lips, tongue, or face, and difficulty breathing.
• Angioedema (rapid swelling under the skin) can be triggered or worsened by estrogen, especially in women with a hereditary tendency toward this condition.
• Blood clots in the eye (retinal thrombosis) or optic nerve inflammation can cause vision changes or vision loss.
• Cholestatic jaundice (yellowing of the skin or eyes from bile flow problems) can occur and requires stopping treatment.
• Worsening of migraine, epilepsy, or systemic lupus erythematosus can occur with estrogen use.
• Sudden vision changes, migraine with aura, weakness or numbness on one side of the body, slurred speech, or loss of consciousness may signal a stroke or blood clot and require stopping the medication immediately.
• Seek urgent medical attention for chest pain, sudden shortness of breath, leg swelling or pain, sudden severe headache, vision loss, signs of a stroke, or signs of a severe allergic reaction.

• Use with caution in women with a strong family history of breast cancer, a prior breast biopsy showing atypical cells, or other risk factors for breast cancer.
• Use with caution in women with diabetes or a predisposition to diabetes, since estrogen-progestin therapy can worsen blood sugar and lipid control.
• Use with caution in women with familial high triglycerides, who require closer monitoring and may need lipid-lowering treatment before starting.
• Use with caution in women with a history of liver or gallbladder disease.
• Use with caution in women with hepatic hemangiomas, since estrogen may worsen this condition.
• Use with caution in women with kidney disease, cardiac dysfunction, or asthma, due to the risk of fluid retention.
• Use with caution in women with uterine fibroids (leiomyomata) or a history of endometriosis, since estrogen can cause these conditions to grow or recur.
• Use with caution in women with otosclerosis (a cause of hearing loss).
• Use with caution in women with systemic lupus erythematosus or a personal or family history of blood clotting disorders.
• Use with caution in women with varicose veins, and consider stopping estrogen-progestin therapy at least 4 weeks before major surgery or periods of prolonged immobility to reduce clot risk.
• Monitor blood pressure regularly during treatment, since hormone therapy can raise blood pressure in some women.
• Perform a baseline physical examination, including blood pressure, breast and pelvic exam, Pap smear, mammogram, and blood glucose, calcium, triglyceride, cholesterol, and liver function tests, before starting, with follow-up at 3 to 6 months and at least annually thereafter.

• Contraindicated in patients with known or suspected hypersensitivity to estradiol, norethindrone acetate, or any ingredient in the patch.
• Contraindicated in patients with known or suspected estrogen- or progestin-dependent cancers, such as endometrial cancer.
• Contraindicated in patients with endometrial hyperplasia.
• Contraindicated in patients with known, suspected, or past history of breast cancer.
• Contraindicated in patients with known or suspected pregnancy.
• Contraindicated in patients with active or past venous thromboembolism, such as deep vein thrombosis or pulmonary embolism, or active thrombophlebitis.
• Contraindicated in patients with known blood clotting disorders (thrombophilic disorders).
• Contraindicated in patients with liver dysfunction or disease until liver function tests have returned to normal.
• Contraindicated in patients with undiagnosed abnormal vaginal or uterine bleeding.
• Contraindicated in patients with active or past arterial thromboembolic disease, such as stroke, heart attack, or coronary heart disease.
• Contraindicated in patients with porphyria.
• Contraindicated in patients with partial or complete vision loss due to disease affecting the blood vessels of the eye.
• Contraindicated in patients with classical migraine.
• Contraindicated in patients who are breastfeeding.

• Estalis may reduce the effectiveness of anticoagulant (blood-thinning), antidiabetic, and blood-pressure-lowering medications.
• Liver-enzyme-inducing medications, including barbiturates, hydantoins such as phenytoin, carbamazepine, meprobamate, phenylbutazone, and rifampicin, can lower estradiol levels and reduce the effectiveness of Estalis.
• Medications that inhibit the CYP3A4 liver enzyme, such as ketoconazole, erythromycin, and ritonavir, can raise estradiol blood levels by roughly half.
• Acute alcohol intake can raise circulating estradiol levels during treatment.
• St. John's Wort and certain other herbal products can interfere with steroid hormone metabolism, potentially reducing the effectiveness or safety of Estalis.
• Estrogen-containing products can raise blood levels of cyclosporine, theophylline, and prednisolone, requiring closer monitoring for increased effects of those drugs.
• Estrogen-containing products can increase the clearance of morphine, salicylic acid (aspirin-related), clofibric acid, and temazepam, potentially reducing their effectiveness.
• Lamotrigine blood levels can be significantly reduced when combined with estradiol, which may reduce seizure control in women taking both medications.
• Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine can lower estradiol blood levels through increased metabolism.

• Not applicable; Estalis is a transdermal patch delivered through the skin rather than swallowed, so food and meal timing do not affect its use.

• Apply a new Estalis patch twice weekly, on the same two days each week, rather than at a specific time relative to meals, since the medication is absorbed continuously through the skin.

• Store unused Estalis patches refrigerated between 2°C and 8°C before dispensing; do not freeze.
• After dispensing, patches may be kept at room temperature (20°C to 25°C) and should be used within one month, or kept refrigerated and used before the expiry date, allowing the patch to warm to room temperature before application for proper adhesion.
• Keep each patch sealed in its individual pouch until immediately before use, store away from extreme temperatures, and keep out of the reach and sight of children and pets, both before use and when disposing of used patches.

• Apply a new Estalis patch twice weekly without interruption, rotating the application site and avoiding the breasts, waistline, and any irritated or oily skin.
• Report any unusual vaginal bleeding, breast changes, severe headache, vision changes, leg swelling or pain, or chest pain to your healthcare professional promptly.
• Discuss your personal and family history of breast cancer, blood clots, stroke, heart disease, and liver disease with your healthcare professional before starting and periodically during treatment.
• Attend scheduled follow-up visits, including breast exams, mammograms, and blood tests, to monitor for potential side effects.
• Use Estalis at the lowest dose and for the shortest time needed to control your symptoms, and periodically discuss with your healthcare professional whether continued treatment is still appropriate.
• If a patch falls off before it is due to be changed, reapply it or replace it with a new one and keep your regular twice-weekly schedule.