MYFEMBREE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for MYFEMBREE (MYFEMBREE).
Myfembree is a combination of relugolix (a gonadotropin-releasing hormone receptor antagonist), estradiol (an estrogen), and norethindrone acetate (a progestin). Relugolix suppresses pituitary gonadotropin secretion, reducing ovarian estrogen and progesterone levels, thereby inhibiting ovulation and reducing menstrual bleeding. Estradiol and norethindrone acetate provide hormone replacement to mitigate hypoestrogenic effects and prevent endometrial hyperplasia.
| Metabolism | Relugolix is primarily metabolized by CYP3A4; estradiol is metabolized via CYP1A2, CYP1A1, CYP1B1, and CYP3A4; norethindrone acetate is metabolized by CYP3A4. |
| Excretion | Following oral administration, relugolix, estradiol, and norethindrone acetate are eliminated primarily via feces (relugolix: ~80%, estradiol: ~75%, norethindrone: ~70%) and to a lesser extent in urine (relugolix: ~5%, estradiol: ~5%, norethindrone: ~20%). |
| Half-life | The terminal elimination half-life for relugolix is approximately 61 hours; for estradiol, ~24 hours; for norethindrone, ~10 hours. The extended half-life of relugolix supports once-daily dosing. |
| Protein binding | Relugolix: approximately 70% bound to plasma proteins (mainly albumin). Estradiol: ~98% bound to sex hormone-binding globulin (SHBG) and albumin. Norethindrone: ~97% bound to SHBG and albumin. |
| Volume of Distribution | Relugolix: apparent Vd/F ~170 L (extensive tissue distribution). Estradiol: ~1.2 L/kg; norethindrone: ~3.6 L/kg. |
| Bioavailability | Relugolix: absolute bioavailability not reported, but exposure is dose-proportional; estradiol and norethindrone acetate are well absorbed. The fixed-dose combination tablet is formulated for optimal oral bioavailability. |
| Onset of Action | Onset of clinical effect (reduction in heavy menstrual bleeding) is observed within 1 month of daily oral administration. |
| Duration of Action | Duration of action after discontinuation: suppression of ovarian hormone levels persists for approximately 2–3 weeks, with return of menses typically within 6–8 weeks. |
One tablet (relugolix 40 mg/estradiol 1 mg/norethindrone acetate 0.5 mg) orally once daily.
| Dosage form | TABLET |
| Renal impairment | eGFR 30-89 mL/min: No adjustment. eGFR 15-29 mL/min: Avoid use (insufficient data). eGFR <15 mL/min or dialysis: Contraindicated. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B or C: Contraindicated. |
| Pediatric use | Not indicated; safety and efficacy not established in patients <18 years. |
| Geriatric use | Not indicated for postmenopausal women; no dose adjustment recommended for elderly patients with normal renal/hepatic function, but clinical data limited. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for MYFEMBREE (MYFEMBREE).
| Breastfeeding | Not recommended during breastfeeding. Estradiol and norethindrone acetate are excreted in human milk; potential for serious adverse effects in nursing infant including jaundice, breast enlargement, and decreased milk production. M/P ratio not established. Use alternative contraception and lactation management. |
| Teratogenic Risk | Pregnancy category X. Contraindicated in pregnancy. Estrogen and progestin combinations increase risk of fetal harm, including congenital anomalies (e.g., cardiovascular, neural tube defects) and spontaneous abortion. Exposure during first trimester: elevated risk of major malformations. Exposure later in pregnancy: associated with genital abnormalities in female fetuses, and possible masculinization of female fetuses from progestin component. Discontinue immediately if pregnancy occurs. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Pregnancy","Current or history of thromboembolic disorders","Arterial thrombotic disease (e.g., stroke, MI)","Known thrombophilia","Hormone-sensitive malignancies (e.g., breast cancer)","Undiagnosed abnormal uterine bleeding","Liver disease or impaired liver function (if severe)","Concurrent use with strong CYP3A inhibitors or inducers (relugolix interaction)"]
| Precautions | ["Thromboembolic disorders: Increased risk of venous thromboembolism and arterial thrombosis; discontinue if thrombosis occurs","Bone loss: Use beyond 2 years may cause significant bone mineral density loss; not recommended for use longer than 2 years","Hepatic effects: Elevated liver enzymes; monitor liver function","Cardiovascular risks: Consider cardiovascular risk factors, especially in women over 35 who smoke","Mood changes: Risk of depression; monitor for mood alterations","Uterine bleeding: May cause amenorrhea or irregular bleeding; evaluate if persistent"] |
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| Fetal Monitoring | If inadvertent exposure occurs, perform pregnancy test to confirm pregnancy. Early ultrasound for fetal assessment. Monitor for signs of pregnancy complications. No specific fetal monitoring required beyond standard prenatal care; however, due to teratogenicity, elective termination may be discussed. |
| Fertility Effects | Reversible suppression of ovulation. After discontinuation, fertility returns typically within one cycle. No known permanent effects on fertility. Use for endometriosis-associated pain may improve fertility by reducing disease burden. |