Relugolix, Estradiol Hemihydrate, And Norethindrone Acetate
FDA Drug Information • Also known as: Myfembree
- Brand Names
- Myfembree
- Dosage Form
- TABLET, FILM COATED
- Product Type
- DRUG FOR FURTHER PROCESSING
⚠ Boxed Warning (Black Box)
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 [see Warnings and Precautions ( 5.1 )]. 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 [see Contraindications ( 4 )]. WARNING: THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTS See full prescribing information for complete boxed warning Estrogen and progestin combinations, including MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders, especially in women at increased risk for these events. ( 5.1 ) 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. ( 4 )
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
What Is Relugolix, Estradiol Hemihydrate, And Norethindrone Acetate 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 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
2 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 )] .
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS 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...
Drug Interactions
7 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.
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 )
Pregnancy and Breastfeeding
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,...
Overdosage
10 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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 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).
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.