Relugolix, Estradiol, and Norethindrone (Monograph)

Brand name: Myfembree
Drug class: Antigonadotropins

Introduction

Fixed combination containing relugolix (gonadotropin-releasing hormone [GnRH] receptor antagonist), estradiol (estrogen), and norethindrone acetate (progestin).

Uses for Relugolix, Estradiol, and Norethindrone

Heavy Menstrual Bleeding Associated with Uterine Fibroids

Management of heavy menstrual bleeding associated with uterine fibroids (leiomyomas) in premenopausal women.

Duration of treatment should not exceed 24 months due to risk of potentially irreversible bone loss.

Moderate to Severe Pain Associated with Endometriosis

Management of moderate to severe pain associated with endometriosis in premenopausal women.

Duration of treatment should not exceed 24 months due to risk of potentially irreversible bone loss.

Relugolix, Estradiol, and Norethindrone Dosage and Administration

General

Pretreatment Screening

• Exclude pregnancy prior to initiating treatment and discontinue hormonal contraceptives.

• Assess bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) before initiating treatment.

• Assess patients with a history of mood disorders, depression, or suicidal ideation prior to initiating treatment.

• Screen for liver disease or hepatic impairment.

• Screen for current or history of thromboembolic disorders, and risk for these events.

• Obtain baseline BP measurement.

Patient Monitoring

• Monitor for signs or symptoms of thrombotic, cardiovascular, or cerebrovascular events, and immediately discontinue the drug if these events occur.

• When used to treat heavy menstrual bleeding associated with uterine fibroids, repeat DXA periodically during treatment; for moderate to severe pain associated with endometriosis, repeat DXA annually.

• Monitor for breast cancer according to standard of care (e.g., breast exams, mammography); monitor for other hormone-sensitive cancers.

• Monitor for mood changes and depressive symptoms to assess whether potential risks of continuing treatment outweigh benefits.

• Monitor for signs or symptoms of liver injury.

• Monitor BP in patients with controlled hypertension.

• Perform pregnancy testing if pregnancy is suspected; discontinue treatment if pregnancy is confirmed.

• Monitor blood glucose concentrations in patients with prediabetes or diabetes.

• Monitor serum lipid concentrations and consider discontinuing treatment for worsening hypercholesterolemia or hypertriglyceridemia.

Dispensing and Administration Precautions

• Relugolix is also available as single-agent 120-mg tablets labeled for treatment of advanced prostate cancer.

• Handling and Disposal: Estradiol is a hazardous drug based on reproductive concerns; follow procedures for proper handling (e.g. use of gloves) when handling the oral tablets.

Other General Considerations

• The effect of calcium and vitamin D supplementation on bone loss related to relugolix/estradiol/norethindrone has not been studied, but supplementation may be beneficial for patients with inadequate dietary intake.

Administration

Oral Administration

Administer orally once daily with or without food at approximately the same time each day. Give first dose as soon as possible after onset of menses and within 7 days of start of menses. Total duration of treatment should not exceed 24 months.

If a dose is missed, take the dose as soon as possible within the same day, then resume regular dosing schedule on following day.

Avoid concomitant use of P-gp inhibitors. If concomitant use cannot be avoided, administer relugolix/estradiol/norethindrone at least 6 hours before P-gp inhibitor.

Dosage

Fixed combination tablets of relugolix/estradiol/norethindrone contain relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg; dosage of norethindrone expressed in terms of norethindrone acetate.

Adults

Heavy Menstrual Bleeding Associated with Uterine Fibroids

Oral

Premenopausal women: 1 tablet of relugolix/estradiol/norethindrone (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) once daily. Start therapy as early as possible after menses onset but no later than 7 days after menses has started; total duration of therapy should not exceed 24 months.

Moderate to Severe Pain Associated with Endometriosis

Oral

Premenopausal women: 1 tablet of relugolix/estradiol/norethindrone (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) once daily. Start therapy as early as possible after menses onset but no later than 7 days after menses has started; total duration of therapy should not exceed 24 months.

Special Populations

Hepatic Impairment

Contraindicated in hepatic impairment or liver disease.

Renal Impairment

Manufacturer makes no specific recommendations.

Geriatric Use

Manufacturer makes no specific recommendations.

Cautions for Relugolix, Estradiol, and Norethindrone

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 ingredient in the formulation.

Warnings/Precautions

Warnings

Thromboembolic Disorders and Vascular Events

Estrogen and progestin combination products, including relugolix/estradiol/norethindrone, increase risk of thromboembolic disorders (see Boxed Warning).

Contraindicated in women with current or history of thromboembolic disorders and those at increased risk for these events.

Discontinue relugolix/estradiol/norethindrone immediately if thrombotic, cardiovascular, or cerebrovascular events occur or are suspected.

If ophthalmic complications occur, evaluate for retinal vein thrombosis.

Discontinue relugolix/estradiol/norethindrone at least 4-6 weeks prior to surgery associated with thrombosis. Discontinue for prolonged immobilization.

Other Warnings and Precautions

Osteoporosis and Bone Loss

May reduce bone mineral density (BMD) in some patients; may not be completely reversible upon discontinuance. Increasing duration of treatment may lead to greater BMD loss.

Assess BMD using dual-energy X-ray absorptiometry (DXA) prior to treatment. For heavy menstrual bleeding associated with uterine fibroids, repeat DXA periodically during treatment; annual DXA assessment recommended for moderate to severe pain associated with endometriosis.

If risk of bone loss exceeds potential benefit of treatment, consider discontinuing therapy.

Contraindicated in women with known osteoporosis.

Hormone Sensitive Malignancy

Abnormal mammograms requiring further evaluation reported with estrogen alone or in combination with progestin.

Breast exams and mammography recommended during treatment.

Discontinue relugolix/estradiol/norethindrone if breast cancer or other hormone-sensitive malignancy develops.

Mood Disorders and Suicidal Ideation

Mood disorders, including depression and suicidal ideation reported.

Assess history of mood disorders, depression, or suicidal ideation prior to treatment; monitor for mood changes and depression during treatment.

Refer patients with new or worsening anxiety, depression, or other mood changes to mental health professionals if appropriate.

Advise patients to seek immediate medical attention for suicidal ideation or behavior; reassess risks and benefits of treatment if these events occur.

Liver Injury and Transaminase Elevation

Contraindicated in patients with hepatic impairment or disease.

Instruct patients to promptly seek medical care if signs or symptoms of liver injury develop. May need to discontinue treatment for liver function abnormalities.

Transaminase elevations observed in clincial studies; no patterns identified in time to onset of such elevations.

Gallbladder Disease

Small increase in relative risk of gallbladder disease reported with estrogen treatment.

Consider risk-benefit of treatment in women with prior cholestatic jaundice associated with estrogen use or pregnancy.

Discontinue therapy if signs or symptoms of gallbladder disease or jaundice occur.

Hypertension

Contraindicated in women with uncontrolled hypertension.

Monitor BP during treatment in women with well-controlled hypertension; discontinue therapy if significant increase in BP occurs.

Menstrual Bleeding Changes and Pregnancy Detection

Start relugolix/estradiol/norethindrone as soon as possible and within 7 days after onset of menses; starting later in menstrual cycle may result in irregular or heavy bleeding.

May make pregnancy recognition more difficult due to reduced menstrual bleeding. Test for pregnancy if suspected and discontinue if pregnancy confirmed.

Exclude pregnancy before treatment. Use effective non-hormonal contraception during treatment and for 1 week after the final dose. Do not use hormonal contraceptives during treatment with relugolix/estradiol/norethindrone.

Uterine Fibroid Prolapse or Expulsion

Uterine fibroid prolapse and expulsion reported in patients with heavy menstrual bleeding associated with uterine fibroids.

Warn patients with submucosal uterine fibroids about possibility of prolapse or expulsion. Instruct patients to contact physician if severe bleeding or cramping occur.

Hair Loss

Alopecia, hair loss, and hair thinning reported. Reversibility of hair loss is unknown.

Consider discontinuing therapy if hair loss becomes a concern.

Carbohydrate and Lipid Metabolism Changes

May increase blood glucose concentrations and reduce glucose tolerance. Women with prediabetes or diabetes may require more frequent monitoring.

Increases in total cholesterol and low-density lipoprotein (LDL) cholesterol reported. Estrogens may cause further elevation of triglycerides in patients with pre-existing hypertriglyceridemia, potentially leading to pancreatitis.

Monitor serum lipid concentrations; consider discontinuing the combination therapy if hypercholesterolemia or hypertriglyceridemia worsens.

Hormone and Coagulation Factor Changes

Estrogen and progestin combinations may reduce serum concentrations of free thyroid or corticosteroid hormone. Higher doses of thyroid hormone or corticosteroids may be needed in patients with hypothyroidism or hypoadrenalism, respectively.

Estrogen and progestin combinations may also affect levels of sex hormone binding globulin and coagulation factors.

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylactoid reactions, urticaria, angioedema) reported.

Contraindicated in women with history of hypersensitivity to any components.

Discontinue immediately if hypersensitivity reaction occurs.

Fetal/Neonatal Morbidity and Mortality

Contraindicated during pregnancy. Can cause early pregnancy loss in humans based on mechanism of action and animal findings. No fetal malformations occurred in animals.

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and interactions associated with all 3 components of relugolix/estradiol/norethindrone.

Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.

Specific Populations

Pregnancy

Contraindicated during pregnancy. Can cause early pregnancy loss in humans based on its mechanism of action and animal findings. Discontinue therapy if pregnancy occurs.

No increase in birth defects identified with exposure to estrogens (e.g., estradiol) and progestins (e.g., norethindrone) before conception or during early pregnancy.

Report exposures during pregnancy to MYFEMBREE Pregnancy Exposure Registry by calling 1-855-428-0707.

Lactation

Relugolix distributed into milk in rats; not known whether relugolix or metabolites distributed into human milk.

Estrogen and progestin detected in breast milk of women treated with the drugs Estrogen plus progestin can reduce milk production; can occur at any time, but less likely after breastfeeding well established.

Consider developmental and health benefits of breastfeeding, clinical importance of therapy, and potential adverse effects to nursing infant.

Females and Males of Reproductive Potential

Exclude pregnancy prior to treatment. Use effective non-hormonal contraception during treatment and for 1 week after final dose. Do not use hormonal contraceptives during treatment with relugolix/estradiol/norethindrone.

Pregnancy recognition may be more difficult due to reduced menstrual bleeding. Test for pregnancy if suspected and discontinue if pregnancy confirmed.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Clinical trials did not include any patients ≥65 years of age.

Hepatic Impairment

Contraindicated in patients with hepatic impairment or disease.

Hepatic impairment expected to increase estradiol exposure and risk of estradiol-related adverse events.

Renal Impairment

Relugolix: Systemic exposure not altered in mild, moderate, or severe renal impairment (Cl_cr 15–89 mL/minute). Not evaluated in patients with end-stage renal disease (ESRD) with or without hemodialysis.

Estradiol and norethindrone: Not evaluated in patients with renal impairment.

Manufacturer makes no specific dosing recommendations in renal impairment.

Common Adverse Effects

Most common adverse reactions (≥3%) in women with heavy menstrual bleeding associated with uterine fibroids: vasomotor symptoms, uterine bleeding, alopecia, decreased libido.

Most common adverse reactions (≥3%) in women with moderate to severe pain associated with endometriosis: headache, vasomotor symptoms, mood disorders, abnormal uterine bleeding, nausea, toothache, back pain, decreased sexual desire and arousal, arthralgia, fatigue, dizziness.

Drug Interactions

Relugolix is a substrate of CYP isoenzymes 3A and 2C8, and an inducer of 3A and 2B6.

Relugolix does not inhibit CYP1A2, 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); it 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).

Drugs Affecting P-gp Transport

Concurrent administration of relugolix/estradiol/norethindrone and P-gp inhibitors (e.g., erythromycin) increases plasma concentrations of relugolix. Avoid concomitant use; if concomitant use is necessary, administer relugolix/estradiol/norethindrone at least 6 hours prior to the P-gp inhibitor and monitor for adverse events.

Drugs Affecting Both P-gp Transport and Hepatic Microsomal Enzymes

Concomitant use of relugolix/estradiol/norethindrone and combined P-gp and strong CPY3A inducers (e.g., rifampin) decreases AUC and peak plasma concentrations of relugolix, estradiol, and/or norethindrone. Avoid concomitant use.

Protein-bound Drugs

Estrogen and progestin combinations can raise serum binding protein concentrations, which may reduce serum free concentrations of thyroid and corticosteroid hormones. Consider higher dosages of thyroid hormone or corticosteroid when used concomitantly with relugolix/estradiol/norethindrone.

Specific Drugs

Relugolix, Estradiol, and Norethindrone Pharmacokinetics

Absorption

Bioavailability

Relugolix: Absolute bioavailability 12%; peak plasma concentrations reached at approximately 2 hours.

Estradiol: Peak plasma concentrations reached at approximately 7 hours.

Norethindrone: Peak plasma concentrations reached at approximately 1 hour.

Steady-state reached within 12 days for relugolix and within 2 weeks for estradiol and norethindrone.

Food

No clinically meaningful changes to exposure of relugolix, estradiol, or norethindrone when administered after a high-fat, high-calorie meal.

Distribution

Extent

Relugolix: Not known whether distributed in human milk.

Estrogen, norethindrone: Distributed into human milk.

Plasma Protein Binding

Relugolix: 68-71% (mainly to albumin; alpha-1-glycoprotein to lesser extent).

Estradiol: 36-37% to sex hormone binding globulin; 61% to albumin; 1-2% unbound.

Norethindrone: 36% to sex hormone binding globulin; 61% to albumin.

Elimination

Metabolism

Relugolix: Metabolized primarily by CYP3A and to a lesser extent by CYP2C8.

Estradiol: hepatic conversion (estradiol reversibly converted to estrone, both converted to estriol); enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption.

Norethindrone: extensive biotransformation by reduction (primary), sulfation by sulfotransferases, glucuronidation by glucuronosyltransferases, and oxidation by CYP enzymes (e.g. CYP3A4); sulfate metabolites most prevalent in systemic circulation.

Elimination Route

Relugolix: Mainly excreted in feces as metabolites (4.2% as unchanged drug); 4.2% excreted in urine (2.2% as unchanged drug).

Estradiol: Excreted in urine as glucuronide and sulfate conjugates.

Norethindrone: Primarily excreted in urine as polar metabolites.

Half-life

Relugolix: 61.5 hours (terminal).

Estradiol: 16.6 hours (terminal).

Norethindrone: 10.9 hours (terminal).

Special Populations

Renal impairment: No clinically significant differences in pharmacokinetics of relugolix in mild to severe renal impairment (not studied in end-stage renal disease with or without dialysis); estradiol and norethindrone not studied in renal impairment.

No clinically significant pharmacokinetic differences observed based on age, race/ethnicity, or weight.

Stability

Storage

Oral

Tablets

15–30°C.

Dispose of unused tablets properly, preferably through a drug take-back program, if available. If such a program unavailable, follow FDA guidance for disposal in the household trash in an unrecognizable, closed container. Do not flush down the toilet.

Actions

• Fixed combination of relugolix (a gonadotropin-releasing hormone [GnRH] receptor antagonist), estradiol (an estrogen), and norethindrone acetate (a progestin).

• Relugolix is a non-peptide GnRH receptor antagonist.

• Relugolix inhibits release of luteinizing hormone and follicle stimulating hormone by competitively binding GnRH receptors in the pituitary gland, resulting in decreased serum concentrations of estradiol and progesterone.

• Reduced systemic estradiol and progesterone concentrations result in reduced bleeding associated with uterine fibroids and pain associated with endometriosis.

• Estradiol is an estrogen that binds to estrogen receptors on responsive tissues.

• Estradiol replacement may reduce bone resorption, bone loss and other hypoestrogenic effects of relugolix.

• Norethindrone is a progestin that binds to progesterone receptors on responsive tissues.

• Norethindrone may protect the uterus from adverse endometrial effects of unopposed estrogen.

Advice to Patients

• 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.

• 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.

• Advise patients that depression, mood disorders, and suicidal ideation may occur with use. Instruct women with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention.

• Advise women to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice.

• Advise women that alopecia, hair loss, and hair thinning in no specific pattern may occur with . Advise women that hair loss and hair thinning may not resolve completely after stopping treatment. Advise women to contact their healthcare provider if they have concerns about changes to their hair.

• Advise women to use effective nonhormonal contraception while taking and for 1 week after discontinuing treatment and to discontinue therapy if pregnancy is confirmed. Advise patients that relugolix/estradiol/norethindrone may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to relugolix/estradiol/norethindrone during pregnancy.

• 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 relugolix/estradiol/norethindrone.

• Advise women to begin taking relugolix/estradiol/norethindrone as soon as possible after the start of menses but no later than 7 days after menses has started.

• Advise women to take any missed dose of relugolix/estradiol/norethindrone as soon as possible the same day and then resume regular dosing the next day at the usual time.

• Advise women taking oral P-gp inhibitors to take relugolix/estradiol/norethindrone first and separate dosing by at least 6 hours.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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