Relugolix, Estradiol, and Norethindrone Acetate (Monograph)

Brand name: Myfembree
Drug class:
Chemical name: 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea
Molecular formula: C₂₉H₂₇F₂N₇O₅SC₁₈H₂₄O₂C₂₂H₂₈O₃
CAS number: 737789-87-6

Introduction

The combination of relugolix (a gonadotropin-releasing hormone [GnRH] receptor antagonist), estradiol (an estrogen), and norethindrone acetate (a progestin) decreases menstrual blood loss.

Uses for Relugolix, Estradiol, and Norethindrone Acetate

Relugolix, estradiol, and norethindrone acetate has the following uses:

Relugolix, estradiol, and norethindrone acetate is a combination of relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin, and is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

Relugolix, estradiol, and norethindrone acetate has the following limitations of use:

Use of relugolix, estradiol, and norethindrone acetate should be limited to 24 months due to the risk of continued bone loss, which may not be reversible.

Relugolix, Estradiol, and Norethindrone Acetate Dosage and Administration

General

Relugolix, estradiol, and norethindrone acetate is available in the following dosage form(s) and strength(s):

Tablets: fixed-dose combination containing relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Exclude pregnancy and discontinue hormonal contraceptives prior to relugolix, estradiol, and norethindrone acetate initiation.

• Begin taking relugolix, estradiol, and norethindrone acetate as early as possible after the onset of menses, but no later than seven days after menses has started.

• Take one tablet orally once daily at approximately the same time each day, with or without food.

• If a dose of relugolix, estradiol, and norethindrone acetate is missed, take the missed dose as soon as possible the same day and then resume regular dosing the next day at the usual time.

• Avoid concomitant use of relugolix, estradiol, and norethindrone acetate with oral P-gp inhibitors. If concomitant use of oral P-gp inhibitors is unavoidable, take relugolix, estradio, and norethindrone acetate first, at least 6 hours before taking the P-gp inhibitor.

Cautions for Relugolix, Estradiol, and Norethindrone Acetate

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, or norethindrone acetate.

Warnings/Precautions

Thromboembolic Disorders and Vascular Events

Relugolix, estradiol, and norethindrone acetate is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events.

Discontinue relugolix, estradiol, and norethindrone acetate immediately if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. Discontinue relugolix, estradiol, and norethindrone acetate at least 4 to 6 weeks before surgeries associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible.

Discontinue relugolix, estradiol, and norethindrone acetate 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 relugolix, estradiol, and norethindrone acetate, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism (PE), deep-vein thrombosis (DVT), 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.

In Phase 3 placebo-controlled clinical trials in 1066 women treated with relugolix, estradiol, and norethindrone acetate for another indication, 2 thromboembolic events (DVT and PE) occurred in 1 woman with risk factors of obesity and a preceding knee injury and one case was reported for a woman treated with relugolix monotherapy in the postmarketing period.

Bone Loss

Relugolix, estradiol, and norethindrone acetate is contraindicated in women with known osteoporosis. Consider the benefits and risks of relugolix, estradiol, and norethindrone acetate 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 and periodically thereafter. Consider discontinuing relugolix, estradiol, and norethindrone acetate 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. Relugolix, estradiol, and norethindrone acetate 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.

In Phase 3 clinical trials, women treated with relugolix, estradiol, and norethindrone acetate for up to 52 weeks had a decline in lumbar spine BMD of 0.8%.

Hormone-sensitive Malignancies

Relugolix, estradiol, and norethindrone acetate 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 relugolix, estradiol, and norethindrone acetate 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.

Depression, Mood Disorders, and Suicidal Ideation

Promptly evaluate patients with mood changes and depressive symptoms, including shortly after initiating treatment, to determine whether the risks of continued therapy with relugolix, estradiol, and norethindrone acetate 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. Reevaluate the benefits and risks of continuing relugolix, estradiol, and norethindrone acetate if such events occur.

In Phase 3 placebo-controlled clinical trials, as compared to placebo, a greater proportion of women treated with relugolix, estradiol, and norethindrone acetate 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%). Suicidal ideation occurred in women treated with relugolix, estradiol, and norethindrone acetate in placebo-controlled clinical trials conducted for a different indication.

Hepatic Impairment and Transaminase Elevations

Relugolix, estradiol, and norethindrone acetate is contraindicated in patients with known hepatic impairment or disease. Steroid hormones may be poorly metabolized in patients with impaired liver function.

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 relugolix, estradiol, and norethindrone acetate until the liver tests return to normal and relugolix, estradiol, and norethindrone acetate causation has been excluded.

In Phase 3 placebo-controlled clinical trials, elevations (≥3 times the upper limit of the normal [ULN] of the reference range) in alanine aminotransferase (ALT) occurred in 0.4% (1/254) of women treated with relugolix, estradiol, and norethindrone acetate compared with no elevations in placebo-treated women. Elevations ≥3 times the ULN in aspartate aminotransferase (AST) occurred in 0.8% (2/254) of women treated with relugolix, estradiol, and norethindrone acetate compared with 0.4% (1/256) of placebo-treated women. No pattern in time to onset of these liver transaminase elevations was identified.

Gallbladder Disease or History of Cholestatic Jaundice

Discontinue relugolix, estradiol, and norethindrone acetate 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

Relugolix, estradiol, and norethindrone acetate is contraindicated in women with uncontrolled hypertension. For women with well-controlled hypertension, continue to monitor blood pressure and stop relugolix, estradiol, and norethindrone acetate if blood pressure rises significantly.

In one of the two Phase 3 clinical trials (Study L1), more women experienced the adverse reaction of new or worsening hypertension with relugolix, estradiol, and norethindrone acetate as compared to placebo (7% vs. 0.8%).

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy

Exclude pregnancy before initiating relugolix, estradiol, and norethindrone acetate. Start relugolix, estradiol, and norethindrone acetate as early as possible after the start of menses but no later than 7 days after menses has started. If relugolix, estradiol, and norethindrone acetate is initiated later in the menstrual cycle, irregular and/or heavy bleeding may initially occur. Women who take relugolix, estradiol, and norethindrone acetate 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 relugolix, estradiol, and norethindrone acetate if pregnancy is confirmed.

Advise women of reproductive potential to use effective non-hormonal contraception during treatment with relugolix, estradiol, and norethindrone acetate and for one week after the final dose. Avoid concomitant use of hormonal contraceptives with relugolix, estradiol, and norethindrone acetate. 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 relugolix, estradiol, and norethindrone acetate.

Risk of Early Pregnancy Loss

Relugolix, estradiol, and norethindrone acetate is contraindicated for use in pregnancy. Based on findings from animal studies and its mechanism of action, relugolix, estradiol, and norethindrone acetate 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, respectively.

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 relugolix, estradiol, and norethindrone acetate. In Phase 3 placebo-controlled clinical trials, uterine fibroid prolapse and uterine fibroid expulsion were reported in women treated with relugolix, estradiol, and norethindrone acetate.

Alopecia

Consider discontinuing relugolix, estradiol, and norethindrone acetate if hair loss becomes a concern.

In Phase 3 placebo-controlled clinical trials, more women experienced alopecia, hair loss, and hair thinning (3.5%) with relugolix, estradiol, and norethindrone acetate, compared to placebo (0.8%). In 3 of the 11 affected women treated with relugolix, estradiol, and norethindrone acetate across Phase 3 clinical trials, alopecia was reported as moderate. For one relugolix, estradiol, and norethindrone acetate-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 relugolix, estradiol, and norethindrone acetate-treated women with prediabetes and diabetes may be necessary. Relugolix, estradiol, and norethindrone acetate may decrease glucose tolerance and result in increased blood glucose concentrations.

Monitor lipid levels and consider discontinuing relugolix, estradiol, and norethindrone acetate 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 relugolix, estradiol, and norethindrone acetate 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

Relugolix, estradiol, and norethindrone acetate is contraindicated in women with a history of hypersensitivity reactions to relugolix or any component of relugolix, estradiol, and norethindrone acetate. Immediately discontinue relugolix, estradiol, and norethindrone acetate if a hypersensitivity reaction occurs.

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to relugolix, estradiol, and norethindrone acetate during pregnancy. Pregnant females exposed to relugolix, estradiol, and norethindrone acetate and healthcare providers are encouraged to call the Myfembree Pregnancy Exposure Registry at 1-(855) 428-0707.

Risk Summary: Relugolix, estradiol, and norethindrone acetate is contraindicated in pregnancy. Based on findings from animal studies and its mechanism of action, relugolix, estradiol, and norethindrone acetate may cause early pregnancy loss. Discontinue relugolix, estradiol, and norethindrone acetate if pregnancy occurs during treatment.

The limited human data with the use of relugolix, estradiol, and norethindrone acetate in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

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.

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 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.

Animal Data: In an embryofetal 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 embryofetal 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).

Lactation

Risk Summary: There are no data on the presence of relugolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Relugolix was detected in milk in lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

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.

The developmental and health benefits of breast-feeding should be considered along with the woman's clinical need for relugolix, estradiol, and norethindrone acetate and any potential adverse effects on the breastfed child from relugolix, estradiol, and norethindrone acetate or from the underlying maternal condition.

Animal Data: In lactating rats administered a single oral dose of 30 mg/kg radiolabeled relugolix on postpartum day 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higher than in plasma at 2 hours post-dose.

Females and Males of Reproductive Potential

Based on animal data and the mechanism of action, relugolix, estradiol, and norethindrone acetate can cause early pregnancy loss if relugolix, estradiol, and norethindrone acetate is administered to pregnant women.

Pregnancy Testing: Relugolix, estradiol, and norethindrone acetate may delay the ability to recognize pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding. Exclude pregnancy before initiating treatment with relugolix, estradiol, and norethindrone acetate. Perform pregnancy testing if pregnancy is suspected during treatment with relugolix, estradiol, and norethindrone acetate and discontinue treatment if pregnancy is confirmed.

Contraception: Advise women of reproductive potential to use effective nonhormonal contraception during treatment with relugolix, estradiol, and norethindrone acetate and for 1 week following discontinuation. Avoid concomitant use of hormonal contraceptives with relugolix, estradiol, and norethindrone acetate. The use of estrogen-containing hormonal contraceptives may increase the risk of estrogen-associated adverse events and is expected to decrease the efficacy of relugolix, estradiol, and norethindrone acetate.

Pediatric Use

Safety and effectiveness of relugolix, estradiol, and norethindrone acetate in pediatric patients have not been established.

Hepatic Impairment

Relugolix, estradiol, and norethindrone acetate is contraindicated in women with hepatic impairment or disease. The use of estradiol (a component of the drug) in patients with hepatic impairment is expected to increase the exposure to estradiol and increase the risk of estradiol-associated adverse reactions.

Common Adverse Effects

Most common adverse reactions (incidence ≥3%) are hot flush, hyperhidrosis or night sweats, uterine bleeding, alopecia, and decreased libido.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Avoid use of relugolix, estradiol, and norethindrone acetate with oral P-gp inhibitors.

• Avoid use with combined P-gp and strong CYP3A inducers, as the exposure of the components of relugolix, estradiol, and norethindrone acetate may be decreased.

Actions

Mechanism of Action

The drug is a combination of relugolix, estradiol, and norethindrone acetate.

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.

Estradiol acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of relugolix, estradiol, and norethindrone acetate, 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 relugolix, estradiol, and norethindrone acetate, norethindrone may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• 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 relugolix, estradiol, and norethindrone acetate 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 patients that relugolix, estradiol, and norethindrone acetate may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise patients to use effective nonhormonal contraception while taking relugolix, estradiol, and norethindrone acetate and to discontinue relugolix, estradiol, and norethindrone acetate if pregnancy is diagnosed. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to relugolix, estradiol, and norethindrone acetate during pregnancy.

• Advise women that alopecia, hair loss, and hair thinning in no specific pattern may occur with relugolix, estradiol, and norethindrone acetate. Advise women that hair loss and hair thinning may not resolve completely after stopping relugolix, estradiol, and norethindrone acetate. 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 relugolix, estradiol, and norethindrone acetate and for one week after discontinuing treatment and to discontinue relugolix, estradiol, and norethindrone acetate if pregnancy is confirmed. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to relugolix, estradiol, and norethindrone acetate 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, and norethindrone acetate.

• Advise women to begin taking relugolix, estradiol, and norethindrone acetate 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, and norethindrone acetate 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, and norethindrone acetate first and separate dosing by at least 6 hours.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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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