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; 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 yr 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 yr
;
Osteoporosis;
Current or history of breast cancer or other hormone-sensitive malignancy;
↑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 1st 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). If arterial or venous thrombotic event occurs or is suspected, immediately discontinue therapy. Risk is ↑ in women >35 yr who smoke and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity. For surgery associated with ↑ thromboembolism risk or prolonged immobilization, discontinue therapy; ≥4–6 wk before surgery, if feasible.
Assess bone mineral density 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 during therapy. Consider discontinuing therapy if risk associated with bone loss exceeds potential benefit of therapy. May add calcium and vitamin D supplement to ↑ bone mineral density.
Assess for history of suicidal ideation, depression, and mood disorders before starting and just after initiating therapy to determine if risks of therapy outweigh benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health provider. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Re-evaluate the benefits and risks of continuing relugolix/estradiol/norethindrone if such events occur.
Monitor for signs/symptoms of hypersensitivity reaction (anaphylaxis, urticaria, angioedema). If hypersensitivity reaction occurs, immediately discontinue relugolix/estradiol/norethindrone.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
- May ↓ glucose tolerance and ↑ blood glucose.
- Monitor lipid levels. May ↑ cholesterol and triglycerides.
- May ↑ serum concentrations of binding proteins (thyroid-binding globulin, corticosteroid-binding globulin), which may ↓ free thyroid or corticosteroid hormone levels.

Implementation ⬆ ⬇

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

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication. Advise patient to read Patient Information before starting therapy.
Instruct patient to take missed dose as soon as possible the same day and then resume regular scheduled dosing.
Inform patient of the potential for bone loss and possible need for supplementation with calcium and vitamin D.
Discuss with patient the possibility of hair loss. Explore methods of coping including discontinuing therapy.
Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications.
Advise patient to notify health care provider immediately if signs and symptoms of thromboembolism (leg pain or swelling; sudden shortness of breath; double vision; bulging of eyes; sudden blindness; pain or pressure in chest, arm, or jaw; sudden, severe headache; weakness or numbness in arm or leg; trouble speaking) occur.
Advise patient to notify health care provider immediately if suicidal thoughts or attempts, new or worse depression or anxiety, other changes in behavior or mood, or liver problems (jaundice, dark, amber-colored urine, feeling tired, nausea, vomiting, generalized swelling, right upper abdomen pain, bruising easily) occur.
Rep: May cause early pregnancy loss if administered to pregnant women. Advise women of reproductive potential to use effective nonhormonal contraception during therapy and for one wk after final dose. Avoid concurrent use of hormonal contraceptives containing estrogen during therapy; may ↑ risk of estrogen-associated adverse events and ↓ efficacy of relugolix/estradiol/norethindrone. Women who take relugolix/estradiol/norethindrone may experience amenorrhea or a ↓ in amount, intensity, or duration of menstrual bleeding, which may delay ability to recognize pregnancy. Inform patient of pregnancy exposure registry and call or encourage patient to call the Myfembree Pregnancy Exposure Registry at 1-855-428-0707.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇