Myfembree (relugolix/estradiol/norethindrone acetate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Relugolix, estradiol, and norethindrone acetate (relugolix/estradiol/norethindrone) is a fixed combination of relugolix (a gonadotropin-releasing hormone (GnRH) receptor antagonist), estradiol (an estrogen), and norethindrone acetate (a progestin).
Relugolix, estradiol, and norethindrone acetate (relugolix/estradiol/norethindrone) is a fixed combination of relugolix (a gonadotropin-releasing hormone (GnRH) receptor antagonist), estradiol (an estrogen), and norethindrone acetate (a progestin).
Relugolix is a non-peptide, dose-dependent, GnRH receptor antagonist. The drug competitively binds to pituitary GnRH receptors, decreasing the release of luteinizing hormone and follicle-stimulating hormone, which thereby reduce circulating concentrations of estradiol and progesterone. Reduction of serum estrogen and progesterone concentrations results in decreased bleeding associated with uterine fibroids and reduced pain associated with endometriosis.
Estradiol is an estrogen that binds to estrogen receptors on responsive tissues, and norethindrone is a progestin that binds to progesterone receptors on responsive tissues. Estradiol and norethindrone are included in the fixed combination of relugolix/estradiol/norethindrone as hormonal ''add-back therapy'' to offset the adverse effects associated with relugolix and estradiol, respectively. The dosage of estradiol in relugolix/estradiol/norethindrone targets an estradiol concentration within the early follicular phase of the menstrual cycle.
Estradiol may reduce bone resorption and bone loss, as well as other adverse effects such as hot flushes and lipid changes, associated with the hypoestrogenic effects of relugolix. Norethindrone may protect the uterus from potential adverse endometrial effects of unopposed estrogen.
Peak concentrations of relugolix, estradiol, and norethindrone are reached 2, 7, and 1 hours after administration of a single dose of the fixed combination. Relugolix concentrations reach steady-state within 12 days of once-daily dosing; estradiol and norethindrone concentrations reach steady state within 2 weeks. Administering relugolix after a high-calorie, high-fat meal decreased AUC and peak plasma concentrations of the drug by 38% and 55%, respectively; these reductions are not considered clinically meaningful.
Exposure to estradiol and norethindrone are not affected to a clinically meaningful extent by the presence of food. Relugolix is 68% to 71% bound to plasma proteins (primarily albumin, and to a lesser extent alpha-1-acid glycoprotein); approximately 36% and 61% of both estradiol and norethindrone are bound to sex hormone binding globulin and albumin, respectively. After a single dose of the fixed combination, terminal half-life of relugolix, estradiol, and norethindrone are 61.5, 16.6, and 10.9 hours, respectively.
Relugolix is primarily metabolized by CYP3A and to a lesser extent by CYP2C8; the drug is mainly eliminated in the feces (81%, with 4.2% as unchanged drug), with 4.1% eliminated in the urine (2.2% as unchanged drug). Estradiol and norethindrone undergo extensive metabolism; estradiol is excreted in the urine as glucuronide and sulfate conjugates, and norethindrone is primarily excreted in the urine as polar metabolites.
USES: This medication is a combination of 3 ingredients: relugolix, estradiol, and norethindrone. It is used by women who have not gone through menopause to help manage heavy menstrual bleeding due to uterine fibroids or pain due to endometriosis. Relugolix works by decreasing your body's production of certain hormones (luteinizing hormone, follicle-stimulating hormone), which leads to lower amounts of female sex hormones (estrogens).
Estradiol is used to decrease bone loss caused by relugolix, while norethindrone is used to help lessen the risk of cancer of the uterus due to estradiol.
Generic name: relugolix/estradiol/norethindrone acetate
Pronunciation: (REL-ue-GOE-lix/ES-tra-DYE-ol/nor-ETH-in-drone)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Myfembree:
- Heavy Menstrual Bleeding Associated With Uterine Leiomyoma
- Pain Associated With Endometriosis
Also known as: Fibroid-Related Heavy Menstrual Bleeding.
Dosing
Relugolix/estradiol/norethindrone is available as fixed combination tablets containing relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg.
Dosage of norethindrone is expressed in terms of norethindrone acetate.
Administer relugolix/estradiol/norethindrone orally once daily with or without food at approximately the same time each day. The first dose should be given as soon as possible after the onset of menses within 7 days of the start of menses. The recommended total duration of treatment is 24 months.
If a dose of relugolix/estradiol/norethindrone is missed, take the dose as soon as possible within the same day, and then resume the regular dosing schedule on the following day.
Avoid concomitant use of P-glycoprotein (P-gp) inhibitors. If concomitant use cannot be avoided, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor.
Store relugolix/estradiol/norethindrone tablets at 15-30degreesC.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Relugolix is a substrate of cytochrome P-450 (CYP) isoenzymes 3A and 2C8, and an inducer of 3A and 2B6. Relugolix does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4; it does not induce 1A2.
Relugolix is a substrate of P-glycoprotein (P-gp), but not breast cancer resistance protein (BCRP); the drug inhibits P-gp and BCRP. Relugolix does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, MATE2-K, or bile salt exporter pump (BSEP).
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*High risk of arterial, venous thrombotic, or thromboembolic disorders.
*Pregnancy.
*Known osteoporosis.
*Current or history of breast cancer or other hormone-sensitive malignancies.
*Known hepatic impairment or disease.
*Undiagnosed abnormal uterine bleeding.
*Known hypersensitivity to relugolix, estradiol, norethindrone acetate, or any components in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse reactions (incidence >=3%) reported with relugolix/estradiol/norethindrone in women with heavy menstrual bleeding associated with uterine fibroids are vasomotor symptoms, uterine bleeding, alopecia, and decreased libido.
The most common adverse reactions (incidence >=3%) reported with relugolix/estradiol/norethindrone in women with moderate to severe pain associated with endometriosis are headache, vasomotor symptoms, mood disorders, abnormal uterine bleeding, nausea, toothache, back pain, decreased sexual desire and arousal, arthralgia, fatigue, and dizziness.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of relugolix/estradiol/norethindrone combination therapy have not been established in pediatric patients.
Relugolix/estradiol/norethindrone is contraindicated during pregnancy. Relugolix/estradiol/norethindrone can cause early pregnancy loss in humans based on its mechanism of action and animal findings. If pregnancy occurs during treatment, the fixed-combination drug should be discontinued.
Human data are insufficient to determine the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes associated with relugolix/estradiol/norethindrone.
In pregnant rabbits, oral exposure to relugolix at exposures equivalent to approximately half of the maximum recommended human dose (40 mg) during organogenesis resulted in spontaneous abortion and total litter loss. However, in rabbits and rats, relugolix exposures ranging from approximately 0.5 to 300 times the human exposure at recommended dosages did not result in fetal malformations.
No increase in genital or non-genital birth defects has been identified with exposure to estrogens (e.g., estradiol) and progestins (e.g., norethindrone) before conception or during early pregnancy based on data from epidemiologic studies and meta-analyses.
MYFEMBREE Pregnancy Exposure Registry tracks pregnancy outcomes in women exposed to relugolix/estradiol/norethindrone during pregnancy. Patients and providers are encouraged to report exposures during pregnancy by calling 1-855-428-0707.
Relugolix is distributed into milk in rats. It is not known whether relugolix or its metabolites are distributed into human milk, but drugs present in the milk of animals are likely to be present in human milk also. Estrogen and progestin have been detected in the breast milk of women treated with these drugs. Estrogen plus progestin therapy can reduce milk production; reduction in milk production can occur at any time, but is less likely after breastfeeding is well established. The developmental and health benefits of breastfeeding, the clinical importance of the therapy to the woman, and any potential adverse effects to the nursing infants should be considered when making treatment decisions.
The manufacturer makes no specific dosage recommendations for geriatric patients.
Clinical trials evaluating relugolix/estradiol/norethindrone combination therapy did not include any patients 65 years of age or older.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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