Version May 2024
Estrogen and progestin combination products, including relugolix/estradiol/norethindrone, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism, deep vein thrombosis, stroke and myocardial infarction, especially in women at increased risk for these events. Relugolix/estradiol/norethindrone is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women >35 years of age who smoke or women with uncontrolled hypertension.
Endometriosis, moderate to severe pain: Oral: One tablet once daily. Maximum duration of therapy: 24 months. Treatment should be started as soon as possible after the onset of menses, but no later than 7 days after menses has started.
Heavy menstrual bleeding: Oral: One tablet once daily. Maximum duration of therapy: 24 months. Treatment should be started as soon as possible after the onset of menses, but no later than 7 days after menses has started.
Missed doses: If a dose is missed, the dose should be administered as soon as remembered the same day, then resume the regular dosing the next day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling. Also refer to individual monographs.
Use is contraindicated in patients with hepatic impairment. Also refer to individual monographs.
Not approved for use in postmenopausal patients.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults Also see individual agents.
>10%:
Cardiovascular: Vasomotor symptoms (11% to 13%; including flushing, hot flash, hyperhidrosis, night sweats)
Endocrine & metabolic: Increased serum cholesterol (200 to <240 mg/dL: 14%; ≥240 mg/dL: 2%)
Nervous system: Headache (33%)
1% to 10%:
Cardiovascular: Hypertension (≤7%; including exacerbation of hypertension), peripheral edema (2%)
Dermatologic: Alopecia (4%)
Endocrine & metabolic: Decreased libido (3% to 4%), increased LDL cholesterol (130 to <160 mg/dL: 9%; ≥160 mg/dL: ≤2%)
Gastrointestinal: Diarrhea (2%), dyspepsia (2% to 3%), nausea (6%), toothache (6%)
Genitourinary: Abnormal uterine bleeding (6% to 7%), breast cyst (2% to 3%), vaginal dryness (2%)
Nervous system: Dizziness (3%), fatigue (3%), mood disorder (≤9%; including anxiety, depressed mood, depression, emotional lability, irritability, suicidal ideation)
Neuromuscular & skeletal: Arthralgia (4%), back pain (5%)
<1%:
Cardiovascular: Deep vein thrombosis, pulmonary embolism
Gastrointestinal: Cholecystitis, cholelithiasis
Genitourinary: Pelvic pain, uterine fibroids (degeneration, expulsion, prolapse)
Hepatic: Increased serum alanine aminotransferase
Neuromuscular & skeletal: Bone fracture
Frequency not defined:
Cardiovascular: Acute myocardial infarction, thromboembolism
Nervous system: Cerebrovascular accident
Neuromuscular & skeletal: Decreased bone mineral density
Postmarketing:
Dermatologic: Fixed drug eruption, urticaria
Hypersensitivity: Angioedema, nonimmune anaphylaxis
Hypersensitivity (eg, anaphylactic reaction, angioedema) to relugolix, estradiol, norethindrone, or any component of the formulation; pregnancy; osteoporosis; current or history of breast cancer or other hormone-sensitive malignancies, and with increased risk for hormone-sensitive malignancies; known hepatic impairment or disease; with undiagnosed abnormal uterine bleeding.
Use is also contraindicated in patients at high risk of arterial, venous thrombotic, or thromboembolic disorders, including patients >35 years of age who smoke; patients known to have current or history of deep vein thrombosis or pulmonary embolism, 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 if >35 years of age.
Concerns related to adverse effects:
• Alopecia: May cause alopecia. Reversibility is unknown. Consider discontinuation if alopecia becomes a concern.
• Bleeding irregularities: Menstrual bleeding patterns may change, causing a decrease in the amount, intensity, or duration of bleeding. Changes in bleeding patterns may alter the ability to detect pregnancy. Pregnancy testing should be conducted if pregnancy is suspected; discontinue use if pregnancy is confirmed.
• Bone mineral density loss: Associated with bone mineral density (BMD) loss; risk is increased with duration of use and may not be completely reversible following discontinuation. Consider supplementation with calcium and vitamin D. Limit duration of treatment to 24 months to reduce the extent of BMD loss. Use caution in patients with risk factors for osteoporosis, including medications that may decrease BMD.
• Breast cancer: May increase the risk for breast cancer and other hormone-sensitive malignancies. Hormone therapy may be associated with increased breast density and an increase in abnormal mammogram findings requiring further evaluation. Discontinue if a hormone-sensitive malignancy is diagnosed.
• Depression: May increase the risk of suicidal ideation and mood disorders (including depression). Evaluate new or worsening psychiatric symptoms and refer to a mental health care professional if appropriate. Patients should seek immediate medical attention for suicidal ideation and behavior. Consider risks and benefits of therapy if mood disturbances occur.
• Hepatic impairment: Discontinue if jaundice develops during therapy or if liver function becomes abnormal.
• Hypertension: Discontinue if BP rises significantly with use.
• Hypersensitivity: Hypersensitivity reactions (eg, anaphylactic reaction, angioedema, urticaria) have been reported with use; discontinue treatment if hypersensitivity occurs.
• Lipid effects: May adversely affect lipid levels, including serum triglycerides leading to pancreatitis, especially in patients with preexisting hypertriglyceridemia.
• Retinal thrombosis: Discontinue if unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occur and immediately evaluate for retinal thrombosis.
• Thromboembolic disorders: The estradiol/norethindrone component increases the risk of thrombotic or thromboembolic disorders particularly in patients otherwise at high risk. Discontinue use if an arterial or venous thromboembolic event occurs. Age >35 years, hypertension, obesity, and tobacco use increase the risk of thromboembolic events.
Disease-related concerns:
• Diabetes: May impair glucose tolerance; closely monitor patients with diabetes or prediabetes.
• Gallbladder disease: May increase risk of gallbladder disease, especially in patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. Discontinue if jaundice occurs.
• Uterine fibroids: Uterine fibroid prolapse or expulsion may occur in patients with submucosal uterine fibroids.
Special populations:
• Surgical patients: Whenever possible, should be discontinued at least 4 to 6 weeks prior to surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Myfembree: Relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg
No
Tablets (Myfembree Oral)
40-1-0.5 mg (per each): $50.07
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Administer by mouth at the same time each day, with or without food.
Hazardous agent: Estradiol and norethindrone (NIOSH 2016 [group 2]). Relugolix is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug; relugolix may cause reproductive toxicity, teratogenicity, and has a structural and/or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Endometriosis, moderate to severe pain: Management of moderate to severe pain associated with endometriosis in premenopausal patients.
Heavy menstrual bleeding: Management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal patients.
Limitations of use: Use should be limited to 24 months due to the risk of continued bone loss, which may not be reversible.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP1A2 (minor), CYP2C8 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy
Chlorprothixene: Estrogen Derivatives may enhance the adverse/toxic effect of Chlorprothixene. Estrogen Derivatives may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider therapy modification
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination
Elacestrant: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: If coadministration with these narrow therapeutic index/sensitive P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of these P-gp substrates. Risk D: Consider therapy modification
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination
Futibatinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Risk D: Consider therapy modification
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Risk X: Avoid combination
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
Inducers of CYP3A4 (Moderate) and P-glycoprotein: May decrease the serum concentration of Relugolix, Estradiol, and Norethindrone. Risk C: Monitor therapy
Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease the serum concentration of Relugolix, Estradiol, and Norethindrone. Risk X: Avoid combination
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Risk C: Monitor therapy
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapy
Melatonin: Estrogen Derivatives may increase the serum concentration of Melatonin. Risk C: Monitor therapy
MetyraPONE: Estrogen Derivatives may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Risk X: Avoid combination
Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification
Pomalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy
Pretomanid: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Raloxifene: Estrogen Derivatives may enhance the adverse/toxic effect of Raloxifene. Risk X: Avoid combination
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Sotorasib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: Consider avoiding use of sotorasib and narrow therapeutic index/sensitive P-gp substrates. If combined use is unavoidable, monitor for increased toxicities of the substrate and consider a decrease in the substrate dosage. Risk D: Consider therapy modification
Sparsentan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy
Tacrolimus (Systemic): Estrogen Derivatives may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
Tranexamic Acid: Estrogen Derivatives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy
Discontinue hormonal contraceptives and exclude pregnancy prior to treatment with relugolix/estradiol/norethindrone.
Nonhormonal contraception is recommended during therapy and for 1 week after the last relugolix/estradiol/norethindrone dose.
Use may alter menstrual bleeding patterns, delaying the ability to detect a pregnancy; if pregnancy is suspected during treatment, pregnancy testing is recommended.
Based on information from animal reproduction studies and the mechanism of action, exposure to relugolix/estradiol/norethindrone during pregnancy may cause early pregnancy loss.
Outcome data following inadvertent use of relugolix/estradiol/norethindrone during pregnancy is limited (Giudice 2022).
Use is contraindicated during pregnancy. Discontinue relugolix/estradiol/norethindrone if pregnancy occurs during treatment.
Data collection to monitor pregnancy and infant outcomes following inadvertent exposure to Myfembree is ongoing. Health care providers are encouraged to enroll patients exposed to Myfembree during pregnancy in the Pregnancy Registry (855-428-0707); patients may also enroll themselves.
It is not known if relugolix is present in breast milk. Estrogens and progestins are present in breast milk.
Milk production may be decreased; this risk is increased prior to the establishment of breastfeeding. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Pregnancy status (prior to therapy); pregnancy status during therapy (if pregnancy is suspected); bone mineral density with dual-energy x-ray absorptiometry (prior to therapy and periodically during therapy in patients with heavy menstrual bleeding associated with uterine fibroids; prior to therapy and annually during therapy in patients with moderate to severe pain associated with endometriosis); age appropriate breast and pelvic exams; BP; glycemic control in patients with diabetes or prediabetes; hemoglobin; lipid profile (periodically during therapy); evaluate mental status prior to therapy in patients with a history of depression, suicidal ideation, and mood disorders; monitor for mood changes (including shortly after initiation of therapy); signs and symptoms of hepatic impairment; signs and symptoms of thromboembolic disorders.
Relugolix is a nonpeptide, gonadotropin-releasing hormone antagonist that decreases luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone, reducing bleeding associated with uterine fibroids. Estradiol may reduce the bone loss associated with relugolix. Norethindrone may protect the uterus from adverse endometrial effects of unopposed estrogen.
In women treated for 24 weeks, a ≥50% decrease in menstrual blood loss from baseline, and a volume of menstrual blood loss <80 mL was observed over the last 35 days of treatment (Al-Hendy 2021).
Also refer to individual Estradiol, Norethindrone, and Relugolix monographs for additional information.
Onset: Decreased menstrual bleeding occurs within 4 weeks of initiating treatment in patients with heavy menstrual bleeding associated with uterine fibroids (Al-Hendy 2021). A decrease in dysmenorrhea and nonmenstrual pelvic pain was observed ~4 weeks after treatment initiation with maximal effect at 8 to 12 weeks in patients with moderate to severe endometriosis (Giudice 2022).
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