Reviewed on 2/23/2023

What Is Relugolix-Estradiol-Norethindrone and How Does It Work?

Relugolix-Estradiol-Norethindrone is a combination medication used for the treatment of Uterine Fibroids and Endometriosis Pain. 

What Are the Side Effects Associated with Using Relugolix-Estradiol-Norethindrone?

Common side effects of Relugolix-Estradiol-Norethindrone include:

Serious side effects of Relugolix-Estradiol-Norethindrone include:

  • hives,
  • difficulty breathing,
  • swelling of the face, lips, tongue, or throat,
  • high blood pressure,
  • shortness of breath,
  • rapid breathing,
  • chest, jaw or left arm pain,
  • unusual sweating,
  • confusion,
  • sudden dizziness,
  • fainting,
  • pain, swelling or warmth in the groin or calf,
  • sudden or severe headaches,
  • trouble speaking,
  • weakness on one side of the body,
  • sudden vision changes,
  • rash,
  • lumps in the breast,
  • new or worsening depression,
  • anxiety,
  • unusual changes in behavior,
  • nausea,
  • vomiting,
  • loss of appetite,
  • stomach pain,
  • yellowing of the eyes or skin (jaundice),
  • dark urine,
  • continuous spotting,
  • sudden heavy bleeding,
  • increased thirst,
  • increased urination, and
  • thoughts of self-harm

Rare side effects of Relugolix-Estradiol-Norethindrone include:

  • None 

Seek medical care or call 911 at once if you have the following serious side effects:

  • Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
  • Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
  • Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out. 

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

What Are the Dosages of Relugolix-Estradiol-Norethindrone?

Adult dosage


  • 40 mg/1 mg/0.5 mg

Uterine Fibroids

Adult dosage

  • Take 1 tablet (Relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg) orally every day
  • Start as early as possible after the onset of menses but no later than 7 days after menses has started

Endometriosis Pain

Adult dosage

  • Take 1 tablet (Relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg) orally every day
  • Start as early as possible after the onset of menses, but no later than 7 days after menses has started

Dosage Considerations – Should be Given as Follows: 

  • See “Dosages”

What Other Drugs Interact with Relugolix-Estradiol-Norethindrone?

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

  • Relugolix-Estradiol-Norethindrone has severe interactions with the following drugs:
  • Relugolix-Estradiol-Norethindrone has serious interactions with at least 54 other drugs.
  • Relugolix-Estradiol-Norethindrone has moderate interactions with at least 85 other drugs.
  • Relugolix-Estradiol-Norethindrone has minor interactions with at least 37 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

What Are Warnings and Precautions for Relugolix-Estradiol-Norethindrone?


Effects of drug abuse

  • None

Short-Term Effects

  • See “What Are Side Effects Associated with Using Relugolix-Estradiol-Norethindrone?”

Long-Term Effects

  • See “What Are Side Effects Associated with Using Relugolix-Estradiol-Norethindrone?”


  • Hypersensitivity reactions, including anaphylactoid reactions, urticaria and angioedema, reported; contraindicated with a history of hypersensitivity reactions to Relugolix or any component; 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 the 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 a 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 the 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 [more than thrice the 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 the 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 the 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 it, adjust the 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

Pregnancy and Lactation

  • 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
  • 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 the presence of Relugolix or its metabolites in human milk, its effects on the breastfed children, or its effects on milk production
    • Relugolix was detected in the 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

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