Myfembree (Relugolix, estradiol hemihydrate, and norethindrone acetate): Uses, Dosage, Side Effects & Warnings

Uses

1 INDICATIONS AND USAGE 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 ) ]. 1.2 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 ) ]. 1.3 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 [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6 )].

Dosage and administration

Exclude pregnancy and discontinue hormonal contraceptives prior to MYFEMBREE initiation. ( 2.1 ) Take one tablet orally once daily. ( 2.2 ) 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. ( 2.3 ) If concomitant use of oral P-gp inhibitors is unavoidable, take MYFEMBREE at least 6 hours before taking the P-gp inhibitor ( 2.4 ) 2.1 Prior to Initiation of MYFEMBREE Exclude pregnancy [see Contraindications ( 4 )] . Discontinue hormonal contraceptives [see Warnings and Precautions ( 5.8 )] . 2.2 Recommended Dosage Take one tablet of MYFEMBREE orally once daily at approximately the same time, with or without food [see Clinical Pharmacology ( 12.3 )]. 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 [see Indications and Usage ( 1.3 ), Warnings and Precautions ( 5.2 ), and Adverse Reactions ( 6 )] . 2.3 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. 2.4 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 [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] .

Dosage forms and strengths

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. ( 3 )

Contraindications

4 CONTRAINDICATIONS MYFEMBREE is contraindicated in women: With a high risk of arterial, venous thrombotic, or thromboembolic disorders [see Boxed Warning and Warnings and Precautions ( 5.1 )] . 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. Exposure to MYFEMBREE early in pregnancy may increase the risk of early pregnancy loss [see Warnings and Precautions ( 5.9 ) and Use in Specific Populations ( 8.1 )] . With known osteoporosis, because of the risk of further bone loss [see Warnings and Precautions ( 5.2 )]. With current or history of breast cancer or other hormone-sensitive malignancies, and with increased risk for hormone-sensitive malignancies [see Warnings and Precautions ( 5.3 )] . With known hepatic impairment or disease [see Warnings and Precautions ( 5.5 )] . With undiagnosed abnormal uterine bleeding. With known anaphylactic reaction, angioedema, or hypersensitivity to MYFEMBREE or any of its components. Anaphylactoid reactions, urticaria, and angioedema have been reported [see Warnings and Precautions ( 5.14 ), Adverse Reactions ( 6.2 )]. High risk of arterial, venous thrombotic, or thromboembolic disorder. ( 4 ) Pregnancy. ( 4 ) Known osteoporosis. ( 4 ) Current or history of breast cancer or other hormone-sensitive malignancies. ( 4 ) Known hepatic impairment or disease. ( 4 ) Undiagnosed abnormal uterine bleeding. ( 4 ) Known hypersensitivity to components of MYFEMBREE. ( 4 )

Warnings and precautions

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. ( 5.1 ) 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. ( 5.2 ) Suicidal Ideation and Mood Disorders (Including Depression) : Advise patients to seek medical attention for new onset or worsening depression, anxiety, or other mood changes. ( 5.4 ) Hepatic Impairment and Transaminase Elevations : Counsel patients on signs and symptoms of liver injury. ( 5.5 ) 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. ( 5.7 ) 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. ( 5.8 ) Risk of Early Pregnancy Loss : Can cause early pregnancy loss. Advise women to use effective non-hormonal contraception. ( 5.9 ) Uterine Fibroid Prolapse or Expulsion : Advise patients to seek medical attention for severe uterine bleeding. ( 5.10 ) Hypersensitivity Reactions : Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs. ( 5.14 ) 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 [see Contraindications ( 4 )] . 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. 5.2 Bone Loss MYFEMBREE is contraindicated in women with known osteoporosis [see Contraindications ( 4 )]. 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 [see Adverse Reactions ( 6.1 )] . The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown. 5.3 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 [see Contraindications ( 4 )] . 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. 5.4 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.

Side effects

The following clinically significant adverse reactions are discussed elsewhere in the labeling: Thromboembolic Disorders and Vascular Events [see Warnings and Precautions ( 5.1 )] Bone Loss [see Warnings and Precautions ( 5.2 )] Suicidal Ideation and Mood Disorders (Including Depression) [see Warnings and Precautions ( 5.4 )] Hepatic Impairment and Transaminase Elevations [see Warnings and Precautions ( 5.5 )] Elevated Blood Pressure [see Warnings and Precautions ( 5.7 )] Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy [see Warnings and Precautions ( 5.8 )] Uterine Fibroid Prolapse or Expulsion [see Warnings and Precautions ( 5.10 )] Alopecia [see Warnings and Precautions ( 5.11 )] Effects on Carbohydrate and Lipid Metabolism [see Warnings and Precautions ( 5.12 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.14 )] 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. In women with moderate to severe pain associated with endometriosis, most common adverse reactions (incidence ≥ 3%) are headache, vasomotor symptoms, mood disorders, abnormal uterine bleeding, nausea, toothache, back pain, decreased sexual desire and arousal, arthralgia, fatigue, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sumitomo Pharma America, Inc. at 1-833-696-8268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Heavy Menstrual Bleeding Associated with Uterine Leiomyomas The safety of MYFEMBREE was evaluated in two placebo-controlled clinical trials, Study L1 (LIBERTY 1) and Study L2 (LIBERTY 2), in women with heavy menstrual bleeding associated with uterine fibroids. In these trials, women received a once daily relugolix 40-mg tablet and an over-encapsulated tablet of E2 1 mg and NETA 0.5 mg (relugolix + E2/NETA), which is equivalent to 1 tablet of MYFEMBREE. Across the two trials, 254 women received MYFEMBREE once daily for 24 weeks. Additionally, 256 women received placebo for 24 weeks, and 258 women received relugolix 40-mg monotherapy once daily for 12 weeks followed by MYFEMBREE for 12 weeks [see Clinical Studies ( 14.1 )] . Of these, 476 women were treated with MYFEMBREE in a 28-week extension trial, Study L3 (LIBERTY Extension), for a total treatment duration of up to 12 months. Demographics were similar across the studies; approximately 43% were White, 51% were Black, and approximately 23% were of Hispanic or Latino ethnicity. The mean age at study entry was approximately 42 years (range 19 to 51 years). Of women who completed Study L3, 229 were rerandomized to continue MYFEMBREE or withdraw from therapy (placebo) for an additional 52 weeks (Study L4). Serious Adverse Reactions In Studies L1 and L2, serious adverse reactions were reported in 3.1% of MYFEMBREE-treated women as compared to 2.3% of placebo-treated women. In MYFEMBREE-treated women, serious adverse drug reactions included uterine myoma expulsion and menorrhagia experienced by one woman and uterine leiomyoma (prolapse), cholecystitis, and pelvic pain reported for one woman each. Adverse Reactions Leading to Study Drug Discontinuation In Studies L1 and L2, 3.9% of women treated with MYFEMBREE discontinued therapy due to adverse reactions, as compared to 4.3% receiving placebo. The most common adverse reaction leading to discontinuation of MYFEMBREE was uterine bleeding (1.2%) with an onset usually reported within the first 3 months of therapy. Common Adverse Reactions The most common adverse reactions reported in at least 3% of women treated with MYFEMBREE for heavy menstrual bleeding associated with uterine fibroids and at an incidence greater than placebo during double-blind placebo-controlled treatment are summarized below in Table 1 . Table 1: Adverse Reactions Occurring in 3% or More in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids Treated with MYFEMBREE in Studies L1 and L2 1 Includes hot flush, hyperhidrosis, or night sweats. 2 Includes menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, and menstruation irregular. 3 Includes libido decreased and loss of libido. Adverse Reaction MYFEMBREE (N = 254) % Placebo (N = 256) % Vasomotor symptoms 1 10.6 6.6 Abnormal uterine bleeding 2 6.3 1.2 Alopecia 3.5 0.8 Libido decreased 3 3.1 0.4 In Study L1, more women experienced the adverse reaction of new or worsening hypertension with MYFEMBREE as compared to placebo (7.0% vs. 0.8%). The most common adverse reactions reported during the extension trial, Study L3, were similar to those reported in the placebo-controlled trials. Less Common Adverse Reactions Adverse reactions reported in at least 2% and less than 3% of women with heavy menstrual bleeding associated with uterine fibroids in the MYFEMBREE treated group and greater incidence than placebo included irritability, dyspepsia, and breast cyst. Other important adverse reactions reported in MYFEMBREE-treated women included one serious reaction each of uterine myoma expulsion (0.4%) and uterine leiomyoma (prolapse) (0.4%). Bone Loss The effect of MYFEMBREE on BMD was assessed by DXA. The least squares mean percent changes from baseline in lumbar spine BMD at Month 6 in Studies L1 and L2 are presented below in Table 2 . Table 2: Mean Percent Change (On-Treatment) from Baseline in Lumbar Spine BMD in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids in Studies L1 and L2 at Month 6 Abbreviations: BMD = bone mineral density; CI = confidence interval.

Drug interactions

Avoid use of MYFEMBREE with oral P-gp inhibitors. ( 7.1 ) Avoid use with combined P-gp and strong CYP3A inducers, as the exposure of the components of MYFEMBREE may be decreased. ( 7.1 ) 7.1 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 [see Clinical Pharmacology ( 12.3 )] 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 [see Dosage and Administration ( 2.4 )] . 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 [see Clinical Pharmacology ( 12.3 )] and may decrease the therapeutic effects of MYFEMBREE. Avoid use of MYFEMBREE with combined P-gp and strong CYP3A inducers.

Use in specific populations

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy. Pregnant females exposed to MYFEMBREE and healthcare providers are encouraged to call the MYFEMBREE Pregnancy Exposure Registry at 1-855-428-0707. Risk Summary MYFEMBREE is contraindicated in pregnancy [see Contraindications ( 4 ) and Warnings and Precautions ( 5.9 )]. Based on findings from animal studies and its mechanism of action, MYFEMBREE may cause early pregnancy loss. Discontinue MYFEMBREE if pregnancy occurs during treatment [see Warnings and Precautions ( 5.9 ) and Clinical Pharmacology ( 12.1 )] . The limited human data with the use of MYFEMBREE in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes [see Data ]. In animal reproduction studies, oral administration of relugolix in pregnant rabbits during organogenesis resulted in spontaneous abortion and total litter loss at relugolix exposures about half those at the maximum recommended human dose (MRHD) of 40 mg. 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 MRHD, respectively [see Data ]. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to estrogens and progestins before conception or during early pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. There are insufficient data to conclude whether the presence of uterine fibroids or endometriosis reduces the likelihood of achieving pregnancy or increases the risk of adverse pregnancy outcomes. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis (Days 6 to 18 of gestation) resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (about half the human exposure at the maximum recommended human dose [MRHD] of 40 mg daily, based on AUC). No treatment related malformations were observed in surviving fetuses. No treatment related effects were observed at 3 mg/kg/day (about 0.1-fold the MRHD) or lower. The binding affinity of relugolix for rabbit GnRH receptors is unknown. In a similar embryo-fetal development study, oral administration of relugolix to pregnant rats during the period of organogenesis (Days 6 to 17 of gestation) did not affect pregnancy status or fetal endpoints at doses up to 1000 mg/kg/day (300 times the MRHD), a dose at which maternal toxicity (decreased body weight gain and food consumption) was observed. A no observed adverse effect level (NOAEL) for maternal toxicity was 200 mg/kg/day (86 times the MRHD). In rats, the binding affinity of relugolix for GnRH receptors is more than 1000-fold lower than that in humans, and this study represents an assessment of non-pharmacological targets of relugolix during pregnancy. No treatment related malformations were observed up to 1000 mg/kg/day. In a pre- and postnatal developmental study in pregnant and lactating rats, oral administration of relugolix to rats during late pregnancy and lactation (Day 6 of gestation to Day 20 of lactation) had no effects on pre- and postnatal development at doses up to 1000 mg/kg/day (300 times the MRHD), a dose in which maternal toxicity was observed (effects on body weight gain). A NOAEL for maternal toxicity was 100 mg/kg/day (34 times the MRHD). 8.2 Lactation Risk Summary Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. Relugolix was detected in human breast milk. In a single dose milk-only lactation study in 8 healthy adult lactating women, the mean total amount of relugolix recovered in human breast milk over the first 24 hours was 0.0031 mg and over 120 hours (5 days) was 0.0042 mg following a single, oral, maternal dose of 40 mg. The mean calculated daily infant dose was 0.0006 mg/kg/day using 0.0031mg (the amount recovered in human breast milk over the first 24 hours). The relative infant dose was 0.105% of the maternal weight-adjusted dose of 40 mg. There are no data on the effects of relugolix or its metabolites on the breastfed child, or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for MYFEMBREE and any potential adverse effects on the breastfed child from MYFEMBREE or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Based on animal data and the mechanism of action, MYFEMBREE can cause early pregnancy loss if MYFEMBREE is administered to pregnant women [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing MYFEMBREE may delay the ability to recognize pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding [see Warnings and Precautions ( 5.8 )]. Exclude pregnancy before initiating treatment with MYFEMBREE. Perform pregnancy testing if pregnancy is suspected during treatment with MYFEMBREE and discontinue treatment if pregnancy is confirmed [see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 )].

Pregnancy

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy. Pregnant females exposed to MYFEMBREE and healthcare providers are encouraged to call the MYFEMBREE Pregnancy Exposure Registry at 1-855-428-0707. Risk Summary MYFEMBREE is contraindicated in pregnancy [see Contraindications ( 4 ) and Warnings and Precautions ( 5.9 )]. Based on findings from animal studies and its mechanism of action, MYFEMBREE may cause early pregnancy loss. Discontinue MYFEMBREE if pregnancy occurs during treatment [see Warnings and Precautions ( 5.9 ) and Clinical Pharmacology ( 12.1 )] . The limited human data with the use of MYFEMBREE in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes [see Data ]. In animal reproduction studies, oral administration of relugolix in pregnant rabbits during organogenesis resulted in spontaneous abortion and total litter loss at relugolix exposures about half those at the maximum recommended human dose (MRHD) of 40 mg. 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 MRHD, respectively [see Data ]. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to estrogens and progestins before conception or during early pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. There are insufficient data to conclude whether the presence of uterine fibroids or endometriosis reduces the likelihood of achieving pregnancy or increases the risk of adverse pregnancy outcomes. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis (Days 6 to 18 of gestation) resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (about half the human exposure at the maximum recommended human dose [MRHD] of 40 mg daily, based on AUC). No treatment related malformations were observed in surviving fetuses. No treatment related effects were observed at 3 mg/kg/day (about 0.1-fold the MRHD) or lower. The binding affinity of relugolix for rabbit GnRH receptors is unknown. In a similar embryo-fetal development study, oral administration of relugolix to pregnant rats during the period of organogenesis (Days 6 to 17 of gestation) did not affect pregnancy status or fetal endpoints at doses up to 1000 mg/kg/day (300 times the MRHD), a dose at which maternal toxicity (decreased body weight gain and food consumption) was observed. A no observed adverse effect level (NOAEL) for maternal toxicity was 200 mg/kg/day (86 times the MRHD). In rats, the binding affinity of relugolix for GnRH receptors is more than 1000-fold lower than that in humans, and this study represents an assessment of non-pharmacological targets of relugolix during pregnancy. No treatment related malformations were observed up to 1000 mg/kg/day. In a pre- and postnatal developmental study in pregnant and lactating rats, oral administration of relugolix to rats during late pregnancy and lactation (Day 6 of gestation to Day 20 of lactation) had no effects on pre- and postnatal development at doses up to 1000 mg/kg/day (300 times the MRHD), a dose in which maternal toxicity was observed (effects on body weight gain). A NOAEL for maternal toxicity was 100 mg/kg/day (34 times the MRHD).

Pediatric use

8.4 Pediatric Use Safety and effectiveness of MYFEMBREE in pediatric patients have not been established.

Overdosage

Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. Supportive care is recommended if an overdose occurs. The amount of relugolix, estradiol, or norethindrone removed by hemodialysis is unknown.

Description

11 DESCRIPTION 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

Mechanism of action

12.1 Mechanism of Action 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. Progestins such as norethindrone act by binding to nuclear receptors that are expressed in progesterone-responsive tissues. As a component of MYFEMBREE, norethindrone may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.

How supplied

16.1 How Supplied MYFEMBREE film-coated tablets contain relugolix 40 mg, estradiol (E2) 1 mg, and norethindrone acetate (NETA) 0.5 mg. The tablets are light yellow to yellow, round film-coated tablet with “MVT” on one side and “415” on the other side. MYFEMBREE is supplied in a white, opaque, high-density polyethylene bottle containing 28 tablets with desiccant and closed with an induction-sealed child-resistant cap (NDC Code 72974-415-01). 16.2 Storage and Handling Store at 15ºC to 30ºC (59ºF to 86ºF). Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal. Do NOT flush down the toilet. 16.1 How Supplied MYFEMBREE film-coated tablets contain relugolix 40 mg, estradiol (E2) 1 mg, and norethindrone acetate (NETA) 0.5 mg. The tablets are light yellow to yellow, round film-coated tablet with “MVT” on one side and “415” on the other side. MYFEMBREE is supplied in a white, opaque, high-density polyethylene bottle containing 28 tablets with desiccant and closed with an induction-sealed child-resistant cap (NDC Code 72974-415-01).

Storage

16.2 Storage and Handling Store at 15ºC to 30ºC (59ºF to 86ºF). Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal. Do NOT flush down the toilet.

Patient information

Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Thromboembolic Disorders and Vascular Events Advise patients that use of estrogen and progestin combinations may increase the risk of venous and arterial thrombotic/thromboembolic events, especially in women at high risk for these events [see Boxed Warning , Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . Bone Loss Advise patients about the risk of bone loss. Advise patients that supplementary calcium and vitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate. Advise women that oral iron supplementation should not be taken at the same time as calcium and vitamin D [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )]. Suicidal Ideation and Mood Disorders (Including Depression) Advise patients that depression, mood disorders, and suicidal ideation may occur with MYFEMBREE use. Instruct women with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )]. Hepatic Impairment and Transaminase Elevations Advise women to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice [see Warnings and Precautions ( 5.5 )] . Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy Advise patients that MYFEMBREE may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise patients to use effective non-hormonal contraception while taking MYFEMBREE and to discontinue MYFEMBREE if pregnancy is diagnosed [see Warnings and Precautions ( 5.8 )] . Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy [see Use in Specific Populations ( 8.1 , 8.3 )]. Alopecia Advise women with uterine fibroids that alopecia, hair loss, and hair thinning in no specific pattern may occur with MYFEMBREE. Advise these women that hair loss and hair thinning may not resolve completely after stopping MYFEMBREE. Advise these women to contact their healthcare provider if they have concerns about changes to their hair [see Warnings and Precautions ( 5.11 ) and Adverse Reactions ( 6.1 )] . Females of Reproductive Potential Advise women to use effective non-hormonal contraception while taking MYFEMBREE and for one week after discontinuing treatment and to discontinue MYFEMBREE if pregnancy is confirmed. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy [see Use in Specific Populations ( 8.1 , 8.3 )]. Drug Interactions Advise women to report their use of any other prescription or nonprescription medications or dietary supplements. Co-administration with certain drugs may decrease the therapeutic effects of MYFEMBREE [see Drug Interactions ( 7.1 )]. Administration Instructions Advise women to begin taking MYFEMBREE as soon as possible after the start of menses but no later than 7 days after menses has started [see Dosage and Administration ( 2.2 )]. Advise women to take any missed dose of MYFEMBREE as soon as possible the same day and then resume regular dosing the next day at the usual time [see Dosage and Administration ( 2.3 )]. Advise women taking oral P-gp inhibitors to take MYFEMBREE first and separate dosing by at least 6 hours [see Dosage and Administration ( 2.4 )]. Manufactured by Patheon Inc., 2100 Syntex Court, Mississauga, Ontario L5N 7K9, Canada Distributed by: Sumitomo Pharma America, Inc., 84 Waterford Drive, Marlborough, MA 01752 214846 MS 007

Active ingredients

Relugolix in 1 product
Estradiol Hemihydrate in 1 product
Norethindrone Acetate in 1 product

Myfembree NDC products (1)

NDC	Strength & form	Labeler	Type
72974-415	Relugolix 40 mg/1; Estradiol Hemihydrate 1 mg/1; Norethindrone Acetate .5 mg/1 Tablet, Film Coated	Sumitomo Pharma America, Inc	NDA

Frequently asked questions

What is Myfembree used for?

1 INDICATIONS AND USAGE 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…

What are the side effects of Myfembree?

The following clinically significant adverse reactions are discussed elsewhere in the labeling: Thromboembolic Disorders and Vascular Events [see Warnings and Precautions ( 5.1 )] Bone Loss [see Warnings and Precautions ( 5.2 )] Suicidal Ideation and Mood Disorders (Including Depression) [see Warnings and Precautions ( 5.4 )] Hepatic Impairment and Transaminase Elevations [see Warnings and… See the full label for the complete list.

Who makes Myfembree?

Myfembree is listed by 1 labeler in the FDA NDC directory, including Sumitomo Pharma America, Inc.