Relugolix + Estradiol + Norethindrone

A. Approved Indications

1.        Heavy Menstrual Bleeding Associated with Uterine Fibroids

• Indicated for the treatment of heavy menstrual bleeding in premenopausal women with uterine fibroids.
• Approved duration: Up to 24 months of continuous therapy.

2.        Moderate to Severe Pain Associated with Endometriosis

• Indicated for managing moderate to severe endometriosis-associated pain in premenopausal women.
• Approved for treatment up to 24 months.

B. Clinically Accepted Off-label or Investigational Uses

• May be considered for estrogen-dependent gynecological disorders under specialist supervision (e.g., adenomyosis, non-fibroid-related abnormal uterine bleeding).
• Studied for potential use in hormonal suppression protocols in reproductive endocrinology settings.

Recommended Adult Dosage (Premenopausal Females):

• One fixed-dose oral tablet once daily containing:
• Relugolix 40 mg
• Estradiol 1 mg
• Norethindrone Acetate 0.5 mg

Route: Oral
Frequency: Once daily
Administration: With or without food, at the same time each day

Treatment Duration:

• Uterine fibroids: Maximum of 24 months
• Endometriosis: Maximum of 24 months

Pediatric Use:

• Not indicated in children or adolescents

Geriatric Use:

• Not indicated in postmenopausal women or elderly patients

Renal Impairment:

• Mild to moderate: No dose adjustment required
• Severe impairment: Use with caution; limited clinical data available

Hepatic Impairment:

• Mild to moderate: Caution advised
• Severe impairment: Contraindicated

Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist that blocks the GnRH receptor in the anterior pituitary gland. This action inhibits the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), resulting in decreased ovarian production of estradiol and progesterone. Estradiol is included in the formulation to reduce the hypoestrogenic side effects (such as hot flashes and bone loss) that occur with Relugolix monotherapy. Norethindrone acetate, a synthetic progestin, provides endometrial protection by counteracting unopposed estrogen activity, thus preventing endometrial hyperplasia. Together, the three agents create a balanced hormonal suppression that relieves symptoms of uterine fibroids and endometriosis while minimizing long-term side effects.

Relugolix:

• Absorption: Oral bioavailability ~12%; peak plasma concentration (Tmax) ~2 hours
• Distribution: Volume of distribution ~3821 L; plasma protein binding ~70%
• Metabolism: Primarily metabolized by CYP3A and CYP2C8 enzymes
• Elimination: Half-life ~25 to 65 hours; ~80% excreted in feces, ~4% in urine

Estradiol:

• Absorption: Well absorbed orally
• Metabolism: Metabolized to estrone and estriol; undergoes enterohepatic recirculation
• Elimination: Excreted in urine and feces; half-life ~13–20 hours

Norethindrone Acetate:

• Absorption: Rapidly deacetylated to norethindrone after oral administration
• Metabolism: Metabolized in the liver
• Elimination: Primarily renal; half-life ~5–14 hours

Pregnancy:

• Contraindicated during pregnancy
• Classified as FDA Pregnancy Category X
• May cause fetal harm, miscarriage, or developmental toxicity
• Women of childbearing potential must use non-hormonal contraception during treatment and for at least 1 week after stopping therapy

Lactation:

• It is not known whether the drug or its metabolites are excreted in human milk
• Due to the potential for hormonal effects on a nursing infant and possible suppression of lactation, use during breastfeeding is not recommended

• Primary Class: Gonadotropin-Releasing Hormone (GnRH) Antagonist Combination
• Subclasses:
• Relugolix: Oral GnRH receptor antagonist
• Estradiol: Natural estrogen (systemic hormone replacement)
• Norethindrone Acetate: Synthetic progestin (endometrial protection)

• Known hypersensitivity to Relugolix, Estradiol, Norethindrone Acetate, or excipients
• Current or history of thromboembolic disorders (e.g., DVT, pulmonary embolism, stroke)
• Known or suspected breast cancer or other estrogen/progestin-dependent tumors
• Cerebrovascular or coronary artery disease
• Uncontrolled hypertension
• Severe hepatic impairment
• Undiagnosed abnormal uterine bleeding
• Pregnancy or breastfeeding

• Thromboembolic Risk:
• Estrogens increase the risk of venous thromboembolism, stroke, and myocardial infarction, particularly in women with additional risk factors (e.g., smoking, obesity)
• Bone Mineral Density (BMD):
• Long-term hormone suppression may reduce BMD
• Combination therapy helps mitigate this, but periodic BMD monitoring is advised for patients requiring prolonged treatment
• Mood and Psychiatric Effects:
• Use caution in patients with a history of depression or mood disorders
• Monitor for new or worsening psychiatric symptoms, including suicidal ideation
• Liver Function:
• Avoid in women with severe liver disease
• Monitor liver enzymes in patients with hepatic concerns
• Blood Pressure Monitoring:
• Estrogen may increase blood pressure; periodic monitoring is recommended

Common Side Effects (≥5%):

• Vasomotor: Hot flushes, night sweats
• Reproductive System: Irregular bleeding, amenorrhea, breast tenderness
• Gastrointestinal: Nausea, abdominal pain
• CNS: Headache, insomnia, fatigue, mood changes
• Musculoskeletal: Back pain, joint pain
• Dermatologic: Acne
• General: Weight gain

Serious or Rare Adverse Effects:

• Venous thromboembolism (DVT, PE)
• Stroke or myocardial infarction
• Liver enzyme elevations or hepatic dysfunction
• Depression or suicidal ideation
• Severe allergic reactions (rare)

Onset and Severity:

• Most common side effects occur within the first 1–3 months of treatment
• Generally mild to moderate and tend to stabilize with continued use

Metabolic Pathways:

• Relugolix is primarily metabolized by CYP3A and CYP2C8
• Estradiol and norethindrone undergo hepatic metabolism (including UGT and sulfation pathways)

Major Drug Interactions:

• CYP3A Inducers (e.g., rifampin, carbamazepine): May reduce Relugolix levels → reduced efficacy
• CYP3A Inhibitors (e.g., ketoconazole, ritonavir): May increase Relugolix exposure
• P-glycoprotein (P-gp) inhibitors: May increase absorption of Relugolix
• Estrogen-containing products: Avoid co-administration due to hormonal overlap
• QT-prolonging agents (e.g., sotalol, amiodarone): Use caution due to potential additive QT prolongation risk

Alcohol and Food:

• No clinically significant food interaction
• Alcohol may worsen estrogen-related side effects in sensitive individuals

• FDA Approvals:
• May 2021: Approved under the brand name Myfembree for heavy menstrual bleeding due to uterine fibroids
• August 2022: Approved for moderate to severe pain associated with endometriosis
• EMA Approval:
• Approved as Ryeqo in Europe for uterine fibroids and endometriosis between 2021 and 2022
• Clinical Guidelines:
• Recognized by ACOG and EMAS as a non-surgical, long-term treatment option for uterine fibroids and endometriosis
• Highlighted in recent gynecological treatment updates as an effective oral alternative to GnRH agonist injections

• Recommended Storage Temperature:
• Store at 20°C to 25°C (68°F to 77°F)
• Excursions permitted between 15°C and 30°C
• Humidity and Light Protection:
• Store in original blister packaging
• Protect from moisture and direct light
• Handling Instructions:
• Do not crush or chew tablets
• Keep in blister until administration
• No refrigeration or reconstitution required