MYFEMBREE tablets for oral administration contain a fixed-dose combination of relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg as active ingredients. Relugolix is a non-peptide small molecule, GnRH receptor antagonist. It is a white to off white to slightly yellow solid and is sparingly soluble in water. The chemical name is N-(4-{1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-N-methoxyurea with the empirical formula of C 29 H 27 F 2 N 7 O 5 S and a molecular weight of 623.63. The structural formula is: Estradiol (E2), an estrogen, is present as the hemihydrate (C 18 H 24 O 2 •½H 2 O) which is a white or almost white crystalline powder. Its chemical name is estra-1, 3, 5 ( 10 )-triene-3, 17β-diol with the empirical formula of C 18 H 24 O 2 and a molecular weight of 272.4. The structural formula is: Norethindrone acetate (NETA), a progestin, is a white or yellowish-white crystalline powder. Its chemical name is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate with the empirical formula of C 22 H 28 O 3 and a molecular weight of 340.5. The structural formula is: Each MYFEMBREE (relugolix, estradiol, and norethindrone acetate) film-coated tablet contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, iron oxide yellow, lactose monohydrate, mannitol, magnesium stearate, sodium starch glycolate, titanium dioxide, and triacetin. Relugolix Structural Formula Estradiol Structural Formula Norethindrone Acetate Structural Formula

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). ( 1.1 , 14.1 ) management of moderate to severe pain associated with endometriosis. ( 1.2 , 14.2 ) 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. ( 1.3 , 5.2 , 6 ) 1.1 Heavy Menstrual Bleeding Associated with Uterine Leiomyomas MYFEMBREE is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women [ see Clinical Studies ( 14 ) ]

Moderate to Severe Pain Associated with Endometriosis MYFEMBREE is indicated for the management of moderate to severe pain associated with endometriosis in premenopausal women [ see Clinical Studies ( 14 ) ]

Limitations of Use Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss that may not be reversible .

Tablets: Each tablet of MYFEMBREE contains a fixed-dose combination of relugolix 40 mg, estradiol (E2) 1 mg, and norethindrone acetate (NETA) 0.5 mg. The tablets are light yellow to yellow, round, film-coated, and debossed with “MVT” on one side and “415” on the other side. Tablets: fixed-dose combination containing relugolix 40 mg, estradiol 1 mg and norethindrone acetate 0.5 mg.

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 2.1 Prior to Initiation of MYFEMBREE Exclude pregnancy . Discontinue hormonal contraceptives

Recommended Dosage Take one tablet of MYFEMBREE orally once daily at approximately the same time, with or without food . Start MYFEMBREE as early as possible after the onset of menses but no later than seven days after menses has started [ see Clinical Studies ( 14 ) ]. The recommended total duration of treatment with MYFEMBREE is 24 months

Missed Dose 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

Dosage Modification for Concomitant Use with P-gp Inhibitors Avoid concomitant use of MYFEMBREE with oral P-gp inhibitors. If concomitant use is unavoidable, take MYFEMBREE first and separate dosing by at least 6 hours .

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. Bone Loss : Decreases in bone mineral density (BMD) may not be completely reversible. Baseline BMD assessment is recommended in all women. In women with heavy menstrual bleeding associated with uterine fibroids, periodic BMD assessments are recommended. In women with moderate to severe pain associated with endometriosis, annual BMD assessments are recommended. Assess risk-benefit for women with additional risk factors for bone loss. Suicidal Ideation and Mood Disorders (Including Depression) : Advise patients to seek medical attention for new onset or worsening depression, anxiety, or other mood changes. Hepatic Impairment and Transaminase Elevations : Counsel patients on signs and symptoms of liver injury. Elevated Blood Pressure : Do not use in women with uncontrolled hypertension. For women with well-controlled hypertension, continue to monitor blood pressure and stop MYFEMBREE if blood pressure rises significantly. Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy : Advise women to use non-hormonal contraception during treatment and for one week after discontinuing MYFEMBREE. MYFEMBREE may delay the ability to recognize pregnancy because it alters menstrual bleeding. Perform testing if pregnancy is suspected and discontinue MYFEMBREE if pregnancy is confirmed. Risk of Early Pregnancy Loss : Can cause early pregnancy loss. Advise women to use effective non-hormonal contraception. Uterine Fibroid Prolapse or Expulsion : Advise patients to seek medical attention for severe uterine bleeding. Hypersensitivity Reactions : Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs. 5.1 Thromboembolic Disorders and Vascular Events MYFEMBREE is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events . Discontinue MYFEMBREE immediately if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. Discontinue MYFEMBREE at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible. Discontinue MYFEMBREE immediately if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis as these have been reported in patients receiving estrogens and progestins. Estrogen and progestin combinations, including the estradiol/norethindrone acetate component of MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at high risk for these events. In general, the risk is greatest among women over 35 years of age who smoke and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity. Two thromboembolic events (DVT and PE) occurred in one woman treated for 38 days with MYFEMBREE for moderate to severe pain associated with endometriosis

Bone Loss MYFEMBREE is contraindicated in women with known osteoporosis . Consider the benefits and risks of MYFEMBREE treatment in patients with a history of a low trauma fracture or risk factors for osteoporosis or bone loss, including taking medications that may decrease bone mineral density (BMD) (e.g., systemic or chronic inhaled corticosteroids, anticonvulsants, or chronic use of proton pump inhibitors). Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline. In women with heavy menstrual bleeding associated with uterine fibroids, periodic DXA during treatment with MYFEMBREE is recommended. In women with moderate to severe pain associated with endometriosis, annual DXA is recommended while taking MYFEMBREE. Consider discontinuing MYFEMBREE if the risk associated with bone loss exceeds the potential benefit of treatment. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation for patients with inadequate dietary intake may be beneficial. MYFEMBREE may cause a decrease in BMD in some patients. BMD loss may be greater with increasing duration of use and may not be completely reversible after stopping treatment . The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown

Hormone-Sensitive Malignancies MYFEMBREE is contraindicated in women with current or a history of hormone-sensitive malignancies (e.g., breast cancer) and in women at increased risk for hormone-sensitive malignancies . Discontinue MYFEMBREE if a hormone-sensitive malignancy is diagnosed. Surveillance measures in accordance with standard of care, such as breast examinations and mammography, are recommended. The use of estrogen alone or estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation

Suicidal Ideation and Mood Disorders (Including Depression) Evaluate patients with a history of suicidal ideation, depression, and mood disorders prior to initiating treatment. Monitor patients for mood changes and depressive symptoms including shortly after initiating treatment, to determine whether the risks of continuing therapy with MYFEMBREE outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Re-evaluate the benefits and risks of continuing MYFEMBREE if such events occur. Gonadotropin-releasing hormone receptor antagonists, including MYFEMBREE, have been associated with mood disorders (including depression) and suicidal ideation. In Studies L1 and L2 in women with heavy menstrual bleeding associated with uterine fibroids, a greater proportion of women treated with MYFEMBREE compared with placebo reported depression (including depression, mood swings, and depressed mood) (2.4% vs. 0.8%), irritability (2.4% vs. 0%), and anxiety (1.2% vs. 0.8%) . In Studies S1 and S2 in women with moderate to severe pain associated with endometriosis, a greater proportion of women treated with MYFEMBREE as compared to placebo reported mood disorders (including depression) (9.1% vs. 7.2%). In addition, cases of suicidal ideation were reported with MYFEMBREE use. All women who reported suicidal ideation had a history of depression and/or anxiety

Hepatic Impairment and Transaminase Elevations Contraindication in Patients with Hepatic Impairment MYFEMBREE is contraindicated in patients with known hepatic impairment or disease . Steroid hormones may be poorly metabolized in patients with impaired liver function . Transaminase Elevations Instruct women to promptly seek medical attention for symptoms or signs that may reflect liver injury, such as jaundice or right upper abdominal pain. Acute liver test abnormalities may necessitate the discontinuation of MYFEMBREE use until the liver tests return to normal and MYFEMBREE causation has been excluded. In placebo-controlled clinical trials, in women with uterine fibroids or endometriosis, elevations (≥ 3 times the upper limit of the normal [ULN] of reference range) in alanine aminotransferase (ALT) occurred in 0.4% (1/254) and 0.7% (3/418) of MYFEMBREE-treated women, respectively, as compared to 0% (0/256) and 0.5% (2/416) of placebo-treated women, respectively; moreover, elevations (≥ 3 times ULN of reference range) in aspartate aminotransferase (AST) occurred in 0.8% (2/254) and 0.2% (1/418) of MYFEMBREE-treated women, respectively, as compared to 0.4% (1/256) and 0.5% (2/416) of placebo-treated women, respectively. No patterns in time to onset of these liver transaminase elevations were identified

Gallbladder Disease or History of Cholestatic Jaundice Discontinue MYFEMBREE if signs or symptoms of gallbladder disease or jaundice occur. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy. Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease

Elevated Blood Pressure MYFEMBREE is contraindicated in women with uncontrolled hypertension . For women with well-controlled hypertension, continue to monitor blood pressure and stop MYFEMBREE if blood pressure rises significantly. In the placebo-controlled clinical trials in women with heavy menstrual bleeding associated with uterine fibroids or with moderate to severe pain associated with endometriosis, more women in one study (Study L1; uterine fibroids) experienced the adverse reaction of new or worsening hypertension with MYFEMBREE compared to placebo (7.0% vs. 0.8%)

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy Exclude pregnancy before initiating MYFEMBREE . Start MYFEMBREE as early as possible after the start of menses but no later than 7 days after menses has started. If MYFEMBREE is initiated later in the menstrual cycle, irregular and/or heavy bleeding may initially occur. Women who take MYFEMBREE may experience amenorrhea or a reduction in the amount, intensity, or duration of menstrual bleeding, which may delay the ability to recognize pregnancy. Perform pregnancy testing if pregnancy is suspected and discontinue MYFEMBREE if pregnancy is confirmed . Advise women of reproductive potential to use effective non-hormonal contraception during treatment with MYFEMBREE and for one week after the final dose. Avoid concomitant use of hormonal contraceptives with MYFEMBREE. The use of estrogen-containing hormonal contraceptives can increase estrogen levels which may increase the risk of estrogen-associated adverse events and decrease the efficacy of MYFEMBREE

Risk of Early Pregnancy Loss MYFEMBREE is contraindicated for use in pregnancy . Based on findings from animal studies and its mechanism of action, MYFEMBREE can cause early pregnancy loss. However, in both rabbits and rats, no fetal malformations were present at any dose level tested which were associated with relugolix exposures about half and approximately 300 times exposures in women at the recommended human dose

Uterine Fibroid Prolapse or Expulsion Advise women with known or suspected submucosal uterine fibroids about the possibility of uterine fibroid prolapse or expulsion and instruct them to contact their physician if severe bleeding and/or cramping occurs while being treated with MYFEMBREE. In Studies L1 and L2, uterine fibroid prolapse or uterine fibroid expulsion were reported in women treated with MYFEMBREE

Alopecia Consider discontinuing MYFEMBREE if hair loss becomes a concern . In Phase 3 placebo-controlled clinical trials in women with heavy menstrual bleeding associated with uterine fibroids, 3.5% of MYFEMBREE-treated women experienced alopecia, hair loss, and hair thinning as compared to 0.8% of placebo-treated women. In 3 of the 11 affected women treated with MYFEMBREE across Studies L1 and L2, alopecia was reported as moderate. For one MYFEMBREE-treated woman in the extension trial, alopecia was a reason for discontinuing treatment. No specific pattern of hair loss was described. The majority of affected women completed the study with reported hair loss ongoing. Whether the hair loss is reversible is unknown

Effects on Carbohydrate and Lipid Metabolism More frequent monitoring in MYFEMBREE-treated women with prediabetes and diabetes may be necessary. MYFEMBREE may decrease glucose tolerance and result in increased blood glucose concentrations. Monitor lipid levels and consider discontinuing MYFEMBREE if hypercholesterolemia or hypertriglyceridemia worsens. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations in triglycerides levels leading to pancreatitis. Use of MYFEMBREE is associated with increases in total cholesterol and low-density lipoprotein cholesterol (LDL-C)

Effect on Other Laboratory Results Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy. The use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce free thyroid or corticosteroid hormone levels. The use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, and coagulation factors

Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactoid reactions, urticaria and angioedema, have been reported with MYFEMBREE . MYFEMBREE is contraindicated in women with a history of hypersensitivity reactions to relugolix or any component of MYFEMBREE . Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs.

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

Effect of Other Drugs on MYFEMBREE P-gp Inhibitors Co-administration of MYFEMBREE with P-gp inhibitors increases the AUC and maximum concentration (C max ) of relugolix and may increase the risk of adverse reactions associated with MYFEMBREE. Avoid use of MYFEMBREE with oral P-gp inhibitors. If use is unavoidable, take MYFEMBREE first, separate dosing by at least 6 hours, and monitor patients for adverse reactions . Combined P-gp and Strong CYP3A Inducers Use of MYFEMBREE with combined P-gp and strong CYP3A inducers decreases the AUC and C max of relugolix, estradiol, and/or norethindrone and may decrease the therapeutic effects of MYFEMBREE. Avoid use of MYFEMBREE with combined P-gp and strong CYP3A inducers.