Relugolix + Estradiol + Norethindrone

Indications

Relugolix + Estradiol + Norethindrone is used for: Uterine Fibroids

Adult Dose

Uterine Fibroids Oral Tablet Fixed-dose combination tablet indicated for management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women 1 tablet (relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg) PO once daily Start as early as possible after onset of menses but no later than 7 days after menses has started. Recommended total duration of treatment is 24 months. Hepatic impairment Contraindicated Use of estradiol (E2) in patients with hepatic impairment is expected to increase exposure to E2 and increase the risk of E2-associated adverse reactions

Child Dose

Renal Dose

Renal impairment Estradiol and norethindrone: Not studied Relugolix Mild-to-severe (CrCl 15-89 mL/min): No dosage adjustment required End-stage renal disease with or without hemodialysis: Not studied

Administration

May take with or without food at approximately the same time

Contra Indications

Pregnancy Osteoporosis Current or history of breast cancer or other hormone-sensitive malignancies Hepatic impairment or disease Undiagnosed abnormal uterine bleeding Hypersensitivity to drug or its components High risk of arterial, venous thrombotic, or thromboembolic disorder

Precautions

Thromboembolic disorders and vascular events Estrogen and progestin combination products, including relugolix/estradiol/norethindrone, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI), especially in women at increased risk for these events. 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; 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. Depression, mood disorders, and suicidal ideation Depression (including depression, mood swings, and depressed mood), irritability, anxiety, and suicidal ideation occurred.

Pregnancy-Lactation

Pregnancy 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 Animal data Oral administration of relugolix in pregnant rabbits during organogenesis resulted in spontaneous abortion and total litter loss at relugolix exposures about half those at the maximum recommended human dose (MRHD) of 40 mg In both rabbits and rats, no fetal malformations were present at any dose level tested, which were associated with relugolix exposures of about half and ~300x exposures in women at the MRHD, respectively Lactation There are no data on presence of relugolix or its metabolites in human milk, effects on the breastfed children, or effects on milk production Relugolix was detected in 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

Interactions

Side Effects

Side effects of Relugolix + Estradiol + Norethindrone : >10% Hot flush, hyperhidrosis, or night sweats (10.6%) 1-10% Increased total cholesterol 130 to <160 mg/dL (9.3%) Abnormal uterine bleeding (6.3%) Alopecia (3.5%) Libido decreased (3.1%) Irritability (2-3%) Dyspepsia (2-3%) Breast cyst (2-3%) Depression (2.4%) Irritability (2.4%) Increased total cholesterol >240 mg/dL (1.7%) Increased total cholesterol 160 to <190 mg/dL (1.5%) Anxiety (1.2%) <1% Low trauma fractures (defined as a fall from standing height or less) (0.6%) Increased total cholesterol ≥190 mg/dL (0.5%) Uterine myoma expulsion (0.4%) Uterine leiomyoma (prolapse) (0.4%) Frequency Not Defined Suicidal ideation

Mode of Action

Relugolix Gonadotropin-releasing hormone (GnRH) receptor antagonist; binds to and blocks GnRH receptors in the anterior pituitary gland Blocking GnRH receptors decreases the release of gonadotropins (ie, luteinizing hormone, follicle-stimulating hormone), thereby decreasing the downstream production of estrogen and progesterone by the ovaries in women Estradiol and norethindrone Estradiol: Addition of exogenous estradiol may reduce the increase in bone resorption and resultant bone loss that can occur due to a decrease in circulating estrogen concentrations from relugolix alone Norethindrone: Protect the uterus from the potential adverse endometrial effects of unopposed estrogen