relugolix/estradiol/norethindrone (Rx)

Brand and Other Names:Myfembree
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

relugolix/estradiol/norethindrone

tablet

  • 40mg/1mg/0.5mg

Uterine Fibroids

Fixed-dose combination tablet indicated for management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women

Take 1 tablet (relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg) PO qDay

Start as early as possible after onset of menses but no later than 7 days after menses has started

Recommended total duration of treatment is 24 months

Dosage Modifications

Coadministration with P-gp inhibitors

  • Avoid coadministration with oral P-gp inhibitors
  • If use is unavoidable, take relugolix/estradiol/norethindrone first and separate dosing by at 6 hr

Renal impairment

  • Estradiol and norethindrone: Not studied
  • Relugolix
    • Mild-to-severe (CrCl 15-89 mL/min): No dosage adjustment required
    • End-stage renal disease with or without hemodialysis: Not studied

Hepatic impairment

  • Contraindicated
  • Use of estradiol (E2) in patients with hepatic impairment is expected to increase exposure to E2 and increase the risk of E2-associated adverse reactions

Dosing Considerations

Exclude pregnancy and discontinue hormonal contraceptives prior to initiation

Safety and efficacy not established

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Interactions

Interaction Checker

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                    Adverse Effects

                    >10%

                    Hot flush, hyperhidrosis, or night sweats (10.6%)

                    1-10%

                    Increased total cholesterol 130 to <160 mg/dL (9.3%)

                    Abnormal uterine bleeding (6.3%)

                    Alopecia (3.5%)

                    Libido decreased (3.1%)

                    Irritability (2-3%)

                    Dyspepsia (2-3%)

                    Breast cyst (2-3%)

                    Depression (2.4%)

                    Irritability (2.4%)

                    Increased total cholesterol >240 mg/dL (1.7%)

                    Increased total cholesterol 160 to <190 mg/dL (1.5%)

                    Anxiety (1.2%)

                    <1%

                    Low trauma fractures (defined as a fall from standing height or less) (0.6%)

                    Increased total cholesterol ≥190 mg/dL (0.5%)

                    Uterine myoma expulsion (0.4%)

                    Uterine leiomyoma (prolapse) (0.4%)

                    Frequency Not Defined

                    Suicidal ideation

                    Postmarketing Reports

                    Immune system disorders: Anaphylactoid reaction

                    Skin and SC tissue disorders: Drug eruption

                    Neoplasms, benign, malignant, and unspecified: Uterine leiomyoma degeneration

                    Respiratory, thoracic, and mediastinal disorders: Pulmonary embolism

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                    Warnings

                    Black Box Warnings

                    Thromboembolic disorders and vascular events

                    • Estrogen and progestin combination products, including relugolix/estradiol/norethindrone, 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
                    • Contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women aged ≥35 years who smoke or women with uncontrolled hypertension

                    Contraindications

                    Pregnancy

                    Osteoporosis

                    Current or history of breast cancer or other hormone-sensitive malignancies

                    Hepatic impairment or disease

                    Undiagnosed abnormal uterine bleeding

                    Hypersensitivity to drug or its components

                    High risk of arterial, venous thrombotic, or thromboembolic disorder

                    • Examples include women aged ≥35 years who smoke and known to have
                      • Current or history of DVT or PE
                      • Vascular disease (eg, cerebrovascular disease, coronary artery disease, peripheral vascular disease)
                      • Thrombogenic valvular or thrombogenic rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation)
                      • Inherited or acquired hypercoagulopathies
                      • Uncontrolled hypertension
                      • Headaches with focal neurological symptoms or migraine headaches with aura

                    Cautions

                    Immediately discontinue if a hypersensitivity reaction occurs

                    Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease; discontinue therapy if signs or symptoms of gallbladder disease or jaundice occur; assess the risk-benefit of continuing therapy for women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy

                    New or worsening hypertension occurred; continue to monitor blood pressure (BP) and stop therapy if BP rises significantly

                    Women 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 treatment if pregnancy is confirmed

                    Based on animal studies and mechanism of action, early pregnancy loss may occur

                    Uterine fibroid prolapse and uterine fibroid expulsion reported; advise women with known or suspected submucosal uterine fibroids about the possibility of uterine fibroid prolapse or expulsion and to contact their physician if severe bleeding and/or cramping occur during treatment

                    Discontinue therapy if a hormone-sensitive malignancy is diagnosed; surveillance measures in accordance with standard of care (eg, breast examinations, mammography) are recommended; use of estrogen alone or estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation

                    Thromboembolic disorders and vascular events

                    • Estrogen and progestin combinations, including estradiol/norethindrone acetate, increase the risk of thrombotic or thromboembolic disorders, including PE, DVT, stroke, and MI, especially in women at high risk for these events
                    • Risk is greatest among women aged ≥35 years who smoke, and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity
                    • Discontinue therapy at least 4-6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible
                    • Discontinue therapy immediately
                      • If an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected
                      • 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

                    Bone loss

                    • Bone mineral density (BMD) loss may occur; may be greater with increasing duration of use and may not be completely reversible after stopping treatment
                    • Consider benefits and risks of 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 BMD (eg, systemic or long-term inhaled corticosteroids, anticonvulsants, or long-term use of proton pump inhibitors)
                    • Assessment of BMD by dual-energy X-ray absorptiometry is recommended at baseline and periodically thereafter
                    • Supplementation with calcium and vitamin D was not studied but may be beneficial for patients with inadequate dietary intake
                    • Impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown

                    Depression, mood disorders, and suicidal ideation

                    • Depression (including depression, mood swings, and depressed mood), irritability, anxiety, and suicidal ideation occurred
                    • Promptly evaluate patients with mood changes and depressive symptoms, shortly after initiating treatment, to determine whether the risks of continued therapy outweigh the benefits
                    • Refer patients with new or worsening depression, anxiety, or other mood changes 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 therapy if such events occur

                    Hepatic impairment and transaminase elevations

                    • Contraindicated in patients with known hepatic impairment or disease
                    • Steroid hormones may be poorly metabolized in patients with impaired liver function
                    • Elevations [≥3x ULN] in ALT and AST reported
                    • Instruct women to promptly seek medical attention for symptoms or signs that may reflect liver injury (eg, jaundice, right upper abdominal pain)
                    • Consider discontinuing treatment if acute liver test abnormalities until liver tests return to normal and cause is ruled out

                    Alopecia

                    • Alopecia, hair loss, and hair thinning reported
                    • Consider discontinuing if hair loss becomes a concern
                    • No specific pattern of hair loss was described
                    • Majority of affected women completed study with reported hair loss ongoing
                    • Unknown if hair loss is reversible

                    Effects on carbohydrate and lipid metabolism

                    • May decrease glucose tolerance and result in increased blood glucose concentrations; consider more frequent monitoring in women with prediabetes and diabetes
                    • Estrogen therapy may be associated with elevated triglycerides, leading to pancreatitis, in women with pre-existing hypertriglyceridemia
                    • Increases in total cholesterol and low-density lipoprotein cholesterol (LDL-C) reported
                    • Monitor lipid levels and consider discontinuing if hypercholesterolemia or hypertriglyceridemia worsens

                    Drug interaction overview

                    • Relugolix: Substrate of CYP3A (primarily) and CYP2C8 (minor); substrate of P-gp; inhibitor of BCRP and P-gp
                    • Laboratory results
                      • Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy; use of estrogen and progestin combinations may raise serum concentrations of binding proteins (eg, thyroid-binding globulin, corticosteroid-binding globulin), which may reduce free thyroid or corticosteroid hormone levels
                      • Use of estrogen and progestin may also affect the levels of sex hormone–binding globulin (SHBG) and coagulation factors
                    • P-gp inhibitors
                      • Avoid coadministration
                      • Coadministration increases relugolix AUC and peak plasma concentration; if unable to avoid, adjust time between dosing relugolix and the P-gp inhibitor
                    • Combined P-gp and strong CYP3A inducers
                      • Avoid coadministration
                      • If use is unavoidable, separate dosing
                      • Coadministration decreases AUC and peak plasma concentration of relugolix, estradiol, and/or norethindrone
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                    Pregnancy & Lactation

                    Pregnancy

                    Contraindicated

                    Based on findings from animal studies and its mechanism of action, early pregnancy loss may occur

                    Discontinue if pregnancy occurs during treatment

                    Limited human data with use in pregnant females are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

                    Perform pregnancy testing if pregnancy is suspected during treatment and discontinue treatment if pregnancy is confirmed

                    Contraception for females of reproductive potential

                    • Use effective nonhormonal contraception during treatment and for 1 week following discontinuation
                    • Avoid concomitant use of hormonal contraceptives
                    • 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/norethindrone

                    Animal data

                    • 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 of about half and ~300x exposures in women at the MRHD, respectively

                    Pregnant exposure registry

                    • Registry monitors pregnancy outcomes in women exposed to therapy during pregnancy
                    • Pregnant females exposed to relugolix/estradiol/norethindrone and healthcare providers are encouraged to call the MYFEMBREE Pregnancy Exposure Registry at 1-(855) 428-0707

                    Lactation

                    There are no data on presence of relugolix or its metabolites in human milk, effects on the breastfed children, or effects on milk production

                    Relugolix was detected in milk of 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 breastfeeding women

                    Reduction can occur at any time but is less likely to occur once breastfeeding is well established

                    Pregnancy Categories

                    A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                    B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                    C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                    D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                    X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                    NA: Information not available.

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                    Pharmacology

                    Mechanism of Action

                    Relugolix

                    • Gonadotropin-releasing hormone (GnRH) receptor antagonist; binds to and blocks GnRH receptors in the anterior pituitary gland
                    • Blocking GnRH receptors decreases the release of gonadotropins (ie, luteinizing hormone, follicle-stimulating hormone), thereby decreasing the downstream production of estrogen and progesterone by the ovaries in women

                    Estradiol and norethindrone

                    • Estradiol: 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
                    • Norethindrone: Protect the uterus from the potential adverse endometrial effects of unopposed estrogen

                    Absorption

                    Absolute bioavailability of relugolix is 62%

                    Steady-state reached at

                    • Relugolix: 12 days
                    • Estradiol and norethindrone: 14 days

                    Peak plasma concentration

                    • Relugolix: 26 ng/mL
                    • Unconjugated estradiol: 28 ng/mL
                    • Norethindrone: 3.6 ng/mL

                    Peak plasma time

                    • Relugolix: 2 hr
                    • Unconjugated estradiol: 7 hr
                    • Norethindrone: 1 hr

                    AUC

                    • Relugolix: 198.1 ng·hr/mL
                    • Unconjugated estradiol: 818.7 ng·hr/mL
                    • Norethindrone: 17.5 ng·hr/mL

                    Distribution

                    Blood/plasma ratio: 0.78 (relugolix)

                    Protein bound

                    • Relugolix: 68-71%; albumin (primarily), alpha1-acid glycoprotein (less extent)
                    • Estradiol circulates in the blood bound to SHBG (36-37%) and to albumin (61%), while only ~1-2% is unbound
                    • Norethindrone binds to a similar extent to SHBG (36%) and to albumin (61%)

                    Metabolism

                    Relugolix: Metabolized primarily by CYP3A and to lesser extent by CYP2C8 in vitro

                    Estradiol: Converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite; estrogens also undergo enterohepatic recirculation due to sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption

                    Norethindrone: Undergoes extensive biotransformation, primarily by reduction, in addition to sulfation, glucuronidation, and oxidation, respectively, by sulfotransferases, glucuronosyltransferases, and CYP enzymes, including CYP3A4; majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites

                    Elimination

                    Excretion

                    • Relugolix: Feces (81%; 4.2% unchanged); urine (4.1%; 2.2% unchanged)
                    • Estradiol: Urine as glucuronide and sulfate conjugates
                    • Norethindrone: Primarily excreted in urine as various polar metabolites

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                    Administration

                    Oral Administration

                    Take with or without food at approximately the same time

                    Missed dose: Take dose as soon as possible on the same day and then resume regular dosing schedule and time the next day

                    Storage

                    Store at 15-30ºC (59-86ºF)

                    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

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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

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                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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                    Code Definition
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.