Estradiol, Norethindrone and Relugolix

MYFEMBREE is a combination of relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin, indicated in premenopausal women for the: management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids). management of moderate to severe pain associated with endometriosis. Limitations of Use Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss which may not be reversible.

MYFEMBREE is a combination of relugolix, estradiol (E2), and norethindrone acetate (NETA). Relugolix is a non-peptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased serum concentrations of the ovarian sex hormones estradiol and progesterone and reduced bleeding associated with uterine fibroids and pain associated with endometriosis. Estradiol acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of MYFEMBREE, the addition of exogenous estradiol may reduce the increase in bone resorption and resultant bone loss that can occur due to a decrease in circulating estrogen concentrations from relugolix alone.

Exclude pregnancy and discontinue hormonal contraceptives prior to MYFEMBREE initiation. Take one tablet orally once daily. Take the missed dose of MYFEMBREE as soon as possible the same day and then resume regular dosing the next day at the usual time. If concomitant use of oral P-gp inhibitors is unavoidable, take MYFEMBREE at least 6 hours before taking the P-gp inhibitor

MYFEMBREE is contraindicated in women: With a high risk of arterial, venous thrombotic, or thromboembolic disorders. Examples include women over 35 years of age who smoke and women who are known to have: current or history of deep vein thrombosis or pulmonary embolism vascular disease (e.g., cerebrovascular disease, coronary artery disease, peripheral vascular disease) thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation) inherited or acquired hypercoagulopathies uncontrolled hypertension headaches with focal neurological symptoms or migraine headaches with aura if over 35 years of age Who are pregnant.

Boxed warning (thromboembolic disorders and vascular): Events Estrogen and progestin combinations, including MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke and myocardial infarction (MI), especially in women at increased risk for these events MYFEMBREE is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension. Thromboembolic Disorders and Vascular Events: Discontinue MYFEMBREE if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs. Discontinue MYFEMBREE if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.

The following clinically significant adverse reactions are discussed elsewhere in the labeling: Thromboembolic Disorders and Vascular Events Bone Loss Suicidal Ideation and Mood Disorders (Including Depression) Hepatic Impairment and Transaminase Elevations Elevated Blood Pressure Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy Uterine Fibroid Prolapse or Expulsion Alopecia Effects on Carbohydrate and Lipid Metabolism Hypersensitivity Reactions In women with heavy menstrual bleeding associated with uterine fibroids, most common adverse reactions (incidence ≥ 3%) are vasomotor symptoms, uterine bleeding, alopecia, and decreased libido.

Avoid use of MYFEMBREE with oral P-gp inhibitors. Avoid use with combined P-gp and strong CYP3A inducers, as the exposure of the components of MYFEMBREE may be decreased.

Store at 20ºC to 25ºC (68ºF to 77ºF), excursions permitted to 15ºC to 30ºC (59ºF to 86ºF).