Relugolix + Estradiol + Norethindrone

This is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

This tablet is a combination of relugolix, estradiol (E2) and norethindrone acetate (NETA). Relugolix is a non-peptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby reducing the release of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), leading to decreased serum concentrations of the ovarian sex hormones estradiol and progesterone and reduced bleeding associated with uterine fibroids. Estradiol acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of this tablet, the 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. Progestins such as norethindrone act by binding to nuclear receptors that are expressed in progesterone-responsive tissues. As a component of this tablet, norethindrone may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.

Exclude pregnancy and discontinue hormonal contraceptives prior to this initiation. Orally one tablet once daily. In case of missed dose, need to take as soon as possible the same day and then resume regular dosing the next day at the usual time. If concomitant use of oral P-gp inhibitors is unavoidable, need to take this tablet at least 6 hours before taking the P-gp inhibitor.

Safety and effectiveness of in pediatric patients have not been established.

With medicine: P-gp Inhibitors: Co-administration of this tablet with P-gp inhibitors increases the AUC and maximum concentration (Cmax) of relugolix and may increase the risk of adverse reactions associated with this tablet.

Combined P-gp and Strong CYP3A Inducers: Use of this tablet with combined P-gp and strong CYP3A inducers decreases the AUC and Cmax of relugolix, estradiol and/or norethindrone and may decrease the therapeutic effects of this tablet.

With food and others: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme.

• High risk of arterial, venous thrombotic or thromboembolic disorder.
• Pregnancy.
• Known osteoporosis.
• Current or history of breast cancer or other hormone sensitive malignancies.
• Known hepatic impairment or disease.
• Undiagnosed abnormal uterine bleeding.
• Known hypersensitivity to relugolix, estradiol or norethindrone acetate.

Most common adverse reactions (incidence >3%) are: Hot flush, Hyperhidrosis or night sweats, Uterine bleeding, Alopecia, Decreased libido.

Based on findings from animal studies and its mechanism of action, this may cause early pregnancy loss. Discontinue this tablet, if pregnancy occurs during treatment. There is no data on the presence of relugolix or its metabolites in human milk, the effects on the breastfed child or the effects on milk production. Relugolix was detected in milk in lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

• Thromboembolic disorders and vascular events: Discontinue this tablet, if an arterial or venous thrombotic, cardiovascular or cerebrovascular event occurs.
• Bone Loss: Decreases in Bone Mineral Density (BMD) that may not be completely reversible.
• Depression, mood disorders and suicidal ideation: Advise patients to seek medical attention for new onset or worsening depression, anxiety or other mood changes.
• Risk of early pregnancy loss: Can cause early pregnancy loss. Advise women to use effective non-hormonal contraception.

Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue and withdrawal bleeding. Supportive care is recommended if an overdose occurs. The amount of relugolix, estradiol or norethindrone removed by hemodialysis is unknown.

Gonadotropin-releasing hormone (GnRH) antagonist

Store in a cool (below 30°C) and dry place, away from light & moisture. Keep all medicines out of reach of children.