Treatment of Moderate to Severe:

• Vasomotor Symptoms due to Menopause.

• Symptoms of Vulvar and Vaginal Atrophy due to Menopause.

Estrogens naturally play a key role in the development and maintenance of the female reproductive system and secondary sexual characteristics. Among the different forms of estrogen, estradiol is the most potent and active within human cells.In women of reproductive age, estradiol is primarily produced by the ovaries, with daily secretion varying according to the menstrual cycle. After menopause, estrogen production shifts mainly to peripheral tissues, where androstenedione is converted into estrone, which becomes the predominant circulating estrogen.

Estrogens exert their effects by binding to specific nuclear receptors in target tissues. Two types of estrogen receptors have been identified, and their distribution varies across different tissues.

They also regulate hormone balance through a negative feedback mechanism on the pituitary gland, reducing the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are typically elevated after menopause.

Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women with a history of endometriosis may need a progestogen.

Use estrogen-alone, or in combination with a progestogen at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary.

Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause: Estradiol 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe vasomotor symptoms due to menopause. The lowest effective dose of Estradiol 0.06% for this indication has not been determined.

Before using the canister for the first time, it must be primed. Remove the large canister cover, and fully depress the pump 5 times Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash. After priming, the pump is ready to use. The recommended area of application is the arm. Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder.

Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause: Estradiol 0.06% 1.25 g per day is the single approved dose for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The lowest effective dose of Estradiol 0.06% for this indication has not been determined. When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, first consider the use of topical vaginal products. Before using the canister for the first time, it must be primed.

Remove the large canister cover, and fully depress the pump 5 times. Discard the unused gel by thoroughly rinsing down the sink or placing it in the household trash. After priming, the pump is ready to use. The recommended area of application is the arm. Apply a thin layer over the entire arm on the inside and outside from wrist to shoulder.

Estrogens are partly metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme system. Drugs that induce or inhibit CYP3A4 may therefore alter estrogen metabolism. CYP3A4 inducers such as St. John’s wort, phenobarbital, carbamazepine, and rifampin may decrease estrogen levels in the blood, potentially reducing therapeutic effectiveness and causing irregular uterine bleeding. On the other hand, CYP3A4 inhibitors, including erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may increase estrogen levels, which can raise the risk of adverse effects.

Estradiol should not be used in women with:

• Unexplained abnormal genital bleeding
• Known or suspected breast cancer or history of breast cancer
• Estrogen-dependent tumors
• Active or past history of deep vein thrombosis (DVT) or pulmonary embolism (PE)
• Active or past arterial thromboembolic disorders such as stroke or myocardial infarction
• Known hypersensitivity, including anaphylaxis or angioedema, to estradiol
• Liver disease or impaired liver function
• Known clotting disorders such as protein C, protein S, or antithrombin deficiency

Estradiol is not recommended during pregnancy. Available evidence does not show a significant increase in birth defects when estrogens were used before or early in pregnancy, but its use is still avoided.

Estrogens can pass into breast milk and may reduce milk production. This effect is more likely during early breastfeeding stages. The benefits of breastfeeding should be carefully weighed against the need for treatment and potential risks to the infant.