relugolix/estradiol/norethindrone

Relugolix: reversibly binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland, causing a decrease in the release of luteinizing hormone and follicle-stimulating hormone, which subsequently leads to decreased serum concentrations of estradiol and progesterone; Estradiol: an estrogen that reduces the ↑ in bone resorption and resultant bone loss that can occur due to a ↓ in circulating estrogen concentrations from relugolix; Norethindrone: a progestin that protects the uterus from estrogen-induced endometrial hyperplasia.

Therapeutic effects:

Reduction in menstrual blood loss in premenopausal women with uterine fibroids.
Reduction in pain in premenopausal women with endometriosis.

Pharmacokinetics ⬆ ⬇

Relugolix

Absorption: 12% absorbed following oral administration.

Distribution: Unknown.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme (and to a lesser extent by CYP2C8). Primarily excreted in feces (81%; 4.2% as unchanged drug), with 4.1% excreted in urine (2.2% as unchanged drug).

Half-Life: 61 hr.

Estradiol

Absorption: Well absorbed following oral administration.

Distribution: Widely distributed to tissues.

Metabolism/Excretion: Mostly metabolized by the liver and other tissues. Enterohepatic recirculation occurs, and more absorption may occur from the GI tract.

Half-Life: 16.6 hr.

Norethindrone

Absorption: Rapidly absorbed following oral administration.

Distribution: Widely distributed to tissues.

Metabolism/Excretion: Mostly metabolized by the liver. Metabolites primarily excreted in the urine (>50%), with 20–40% being excreted in feces.

Half-Life: 8–9 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO (relugolix)	unknown	2 hr	unknown
PO (estradiol)	unknown	7 hr	unknown
PO (norethindrone)	unknown	1 hr	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Women >35 years old who smoke;
Current or history of deep vein thrombosis or pulmonary embolism;
Cerebrovascular disease, cardiovascular disease, or peripheral vascular disease;
Subacute bacterial endocarditis with valvular disease or atrial fibrillation;
Inherited or acquired hypercoagulopathies;
Uncontrolled hypertension;
Headaches with focal neurological symptoms or migraine headaches with aura if >35 years old;
Osteoporosis;
Current or history of breast cancer or other hormone-sensitive malignancy;
Increased risk for hormone-sensitive malignancy;
Hepatic impairment;
Undiagnosed abnormal uterine bleeding;
OB: Pregnancy.

Use Cautiously in:

Underlying cardiovascular disease;
Obesity;
History of low trauma fracture or risk factors for osteoporosis or bone loss, including taking medications that may ↓ bone mineral density;
History of suicidal ideation, depression, or anxiety;
Submucosal uterine fibroids (↑ risk of prolapse or expulsion);
Prediabetes or diabetes;
Hypertriglyceridemia;
Hypothyroidism or hypoadrenalism (may need to ↑ doses of thyroid hormone or cortisol replacement therapy;
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: DEEP VEIN THROMBOSIS, edema, hypertension, MI

Derm: hot flush, hyperhidrosis, night sweats, alopecia

Endo: hyperglycemia

GI: ↑liver enzymes, cholecystitis, diarrhea, dyspepsia, nausea

GU: ↓libido, amenorrhea, uterine bleeding, uterine fibroid expulsion/prolapse, vulvovaginal dryness

Metab: hypercholesterolemia, hypertriglyceridemia

MS: ↓bone mineral density, arthralgia

Neuro: headache, anxiety, depression, dizziness, fatigue, irritability, STROKE, SUICIDAL THOUGHTS/BEHAVIORS

Resp: PULMONARY EMBOLISM

Misc: BREAST CANCER, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS AND ANGIOEDEMA)

Interactions ⬆ ⬇

Drug-drug:

Corticosteroids, anticonvulsants, or proton pump inhibitors may ↑ risk of bone mineral density reduction and osteoporosis.
Hormonal contraceptives may ↓ effectiveness of relugolix/estradiol/norethindrone and ↑ risk of thromboembolic events; avoid concurrent use.
P-glycoprotein (P-gp) inhibitors may ↑ relugolix levels and risk of toxicity; avoid concurrent use. If concurrent use unavoidable, administer relugolix/estradiol/norethindrone first and then administer P-gp inhibitor ≥6 hr later.
Combined P-gp and strong CYP3A4 inducers may ↓ relugolix/estradiol/norethindrone levels and effectiveness; avoid concurrent use.

Route/Dosage ⬆ ⬇

PO (Adults ): One tablet once daily. Start as early as possible after the onset of menses but no later than 7 days after menses has started. Duration of therapy not to exceed 24 mo.

Availability ⬆ ⬇

Tablets: relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg

Assessment ⬆ ⬇

Monitor for signs and symptoms of thrombotic events (sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, retinal vascular lesions). Discontinue therapy immediately if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. Assess for retinal vein thrombosis. Risk is greatest among women over 35 yr of age who smoke and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity. Discontinue Myfembree at least 4 to 6 wk before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible.
May cause bone loss. Assess bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) at baseline and periodically in women with heavy menstrual bleeding associated with uterine fibroids. In women with moderate to severe pain associated with endometriosis, annual DXA is recommended while taking Myfembree. Consider discontinuing Myfembree if risk associated with bone loss exceeds the potential benefit of therapy. May add calcium and vitamin D supplement to increase BMD.
Assess patients with a history of suicidal ideation, depression, and mood disorders prior to starting therapy for mood changes and depressive symptoms including shortly after initiating treatment, to determine whether the risks of continuing therapy outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Re-evaluate the benefits and risks of continuing Myfembreeif such events occur.
Monitor for signs and symptoms of hypersensitivity reactions (anaphylaxis, urticaria, angioedema). Immediately discontinue therapy if a hypersensitivity reaction occurs.

Lab Test Considerations:

Validate negative pregnancy test before starting therapy.
- Monitor blood sugar frequently. May decrease glucose tolerance and increase blood glucose.
- Monitor lipid levels and consider discontinuing therapy if hypercholesterolemia or hypertriglyceridemia worsens.

Implementation ⬆ ⬇

Begin therapy as soon as possible after the onset of menses but no later than 7 days after menses has started. If Myfembree is started later in the menstrual cycle, irregular and/or heavy bleeding may initially occur.
Total duration of Myfembree therapy is 24 mo.
PO: Administer one tablet orally once daily at the same time, without regard to food.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take medication as directed at the same time each day. Take missed doses as soon as possible the same day and then resume regular dosing the next day at the usual time. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
Inform patient of the potential for bone loss, including the scans and possible supplementation with calcium and vitamin D.
May cause hair thinning or loss. Discuss with patient the possibility of hair loss. Explore methods of coping. May consider discontinuing therapy.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Advise patient to notify health care professional immediately if signs and symptoms of thromboembolism (leg pain or swelling that will not go away; sudden shortness of breath; double vision; bulging of the eyes; sudden blindness, partial or complete; pain or pressure in your chest, arm, or jaw; sudden, severe headache unlike your usual headaches; weakness or numbness in an arm or leg; trouble speaking); suicidal thoughts (thoughts about suicide or dying, attempts to commit suicide, new or worse depression, new or worse anxiety, other unusual changes in behavior or mood) or liver problems (jaundice, dark, amber-colored urine, feeling tired, nausea and vomiting, generalized swelling, right upper abdomen pain, bruising easily) occur.
Rep: May cause early pregnancy loss if administered to pregnant women. Advise females of reproductive potential to use effective non-hormonal contraception during therapy and for one wk after final dose. Women who take Myfembree may experience amenorrhea or a reduction in amount, intensity, or duration of menstrual bleeding; may delay ability to recognize pregnancy. Avoid concomitant use of hormonal contraceptives with Myfembree. The use of estrogen-containing hormonal contraceptives can increase estrogen levels which may increase risk of estrogen-associated adverse events and decrease the efficacy of Myfembree. Inform patient of pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Myfembree. during pregnancy. Pregnant females exposed to Myfembree. and health care providers are encouraged to call the Myfembree Pregnancy Exposure Registry at 1-855-428-0707.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇