R-Lix

1. Advanced Prostate Cancer (in adult males):

• Indicated for the treatment of adult patients with advanced hormone-sensitive prostate cancer.
• Effective in both metastatic and non-metastatic stages as part of androgen deprivation therapy (ADT).

2. Uterine Fibroids (in premenopausal females, as a combination therapy):

• Used in combination with estradiol and norethisterone acetate to manage heavy menstrual bleeding associated with uterine fibroids.
• Indicated for treatment lasting up to 24 months.

3. Endometriosis (in premenopausal females, as a combination therapy):

• Indicated in combination with estradiol and norethisterone acetate for the management of moderate to severe endometriosis-related pain.
• Approved for up to 24 months of treatment.

B. Clinically Accepted Off-label or Investigational Uses

• Investigated in assisted reproductive technologies (ART) for controlled ovarian suppression.
• Potential use in estrogen-dependent conditions, such as adenomyosis and premenstrual disorders (still under research).
• Short-term hormonal suppression in gynecological procedures or fertility planning.

A. For Advanced Prostate Cancer (Monotherapy)

• Initial dose: 360 mg orally on Day 1
• Maintenance dose: 120 mg orally once daily starting from Day 2
• Take tablets at the same time each day, with or without food.
• No need for concurrent antiandrogens due to rapid testosterone suppression.

B. For Uterine Fibroids (Combination Therapy)

• Relugolix 40 mg + Estradiol 1 mg + Norethisterone acetate 0.5 mg orally once daily
• Duration: Maximum of 24 months
• Take consistently at the same time each day, with or without meals.

C. For Endometriosis (Combination Therapy)

• Same dosage as uterine fibroids:
  Relugolix 40 mg + Estradiol 1 mg + Norethisterone acetate 0.5 mg orally once daily
• Treatment limited to a maximum of 24 months.

D. Pediatric Use:

• Not indicated in pediatric populations.

E. Geriatric Use:

• No dosage adjustment required in elderly patients with prostate cancer unless hepatic or renal impairment is present.

F. Renal Impairment:

• Mild to moderate: No dosage adjustment needed
• Severe: Use with caution; limited data available

G. Hepatic Impairment:

• Mild to moderate: No adjustment required
• Severe impairment: Use not recommended due to insufficient safety data

Relugolix is an orally active, non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist. It works by directly blocking GnRH receptors in the anterior pituitary gland. This inhibition prevents the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a rapid and sustained decrease in circulating testosterone levels in men and estradiol and progesterone levels in women. Unlike GnRH agonists, Relugolix does not cause an initial hormone surge (“flare”) and results in immediate hormonal suppression. This makes it particularly suitable for hormone-sensitive cancers and gynecological disorders.

• Absorption:
• Oral bioavailability: ~12%
• Peak plasma concentration (Tmax): 1 to 2 hours
• Food has minimal effect on absorption
• Distribution:
• Volume of distribution: ~3821 liters
• Plasma protein binding: ~70%
• Metabolism:
• Primarily metabolized by CYP3A and CYP2C8 enzymes
• Minor contributions from glucuronidation (UGT pathways)
• Elimination:
• Elimination half-life: ~25 to 65 hours
• Excreted mainly in feces (~80%); urine excretion ~4%
• No accumulation with once-daily dosing

A. Pregnancy:

• FDA Category X (for female indications)
• Contraindicated in pregnant women due to risk of fetal harm. Relugolix significantly reduces sex hormone levels essential for fetal development.
• Women of childbearing potential must use effective contraception during treatment and for at least one week after discontinuation.

B. Lactation:

• It is not known whether Relugolix is excreted into human breast milk.
• Due to potential effects on hormonal balance and infant development, breastfeeding is not recommended during treatment.
• Women should either discontinue breastfeeding or stop therapy, based on clinical need.

• Primary Class: Gonadotropin-Releasing Hormone (GnRH) Antagonist
• Subclassification: Oral, non-peptide GnRH antagonist
• Indications Class: Androgen deprivation (oncology) and estrogen suppression (gynecology)

• Known hypersensitivity to Relugolix or any component of the formulation
• Pregnancy (due to risk of fetal harm)
• Severe hepatic impairment
• Use in combination with hormonal contraceptives (unless specifically prescribed)
• Women with undiagnosed abnormal genital bleeding

• Cardiovascular:
• Risk of QT interval prolongation; caution in patients with arrhythmia or on QT-prolonging drugs.
• Bone Mineral Density Loss:
• Estrogen/testosterone suppression may lead to bone loss; monitor BMD if long-term therapy is considered.
• Hepatic Impairment:
• Avoid use in severe hepatic dysfunction due to increased drug exposure and lack of safety data.
• Hypoestrogenic or Hypogonadal Symptoms:
• Includes hot flushes, night sweats, mood swings, fatigue, vaginal dryness, or loss of libido.
• Monitoring Needs:
• Monitor hormone levels, bone density (for women), ECG (in high-risk cardiac patients), and liver function during prolonged therapy.

A. Common Adverse Effects:

• Endocrine/Metabolic: Hot flashes, decreased libido, sweating, weight changes
• Musculoskeletal: Arthralgia, back pain, bone density loss
• Gastrointestinal: Nausea, diarrhea, abdominal pain
• Neurologic/Psychiatric: Headache, fatigue, depression, insomnia
• Reproductive (Females): Amenorrhea, vaginal bleeding, breast discomfort
• Reproductive (Males): Erectile dysfunction, gynecomastia (rare)

B. Serious Adverse Effects:

• QT prolongation
• Liver enzyme elevation
• Rare hypersensitivity or anaphylactic reactions
• Depression or suicidal ideation (rare, more common in female indications)

C. Timing and Dose Dependence:

• Symptoms typically appear within the first 2–4 weeks and may persist or intensify with prolonged suppression.
• Dose-related hormonal suppression correlates with adverse effect profile.

A. Major Interactions:

• CYP3A Inducers (e.g., rifampin, carbamazepine):
  May reduce Relugolix plasma concentration and therapeutic effect.
• CYP3A Inhibitors (e.g., ketoconazole, itraconazole):
  May increase Relugolix exposure and risk of side effects.
• CYP2C8 Inhibitors (e.g., gemfibrozil):
  Can also increase drug levels.
• P-glycoprotein (P-gp) Inhibitors (e.g., verapamil, clarithromycin):
  May increase systemic exposure; caution advised.
• QT-Prolonging Agents (e.g., amiodarone, haloperidol):
  Additive risk of QT prolongation.

B. Alcohol:

• No specific contraindications, but chronic alcohol use may impact liver metabolism.

C. Hormonal Contraceptives:

• Avoid co-administration unless clinically justified, due to overlapping hormone suppression.

• FDA Approval Timeline:
• Relugolix (Orgovyx) approved in December 2020 for advanced prostate cancer.
• Combination product (Relugolix + Estradiol + Norethisterone acetate) approved as Myfembree (for uterine fibroids and endometriosis) in 2021–2022.
• NCCN Guidelines (2023–2024):
• Relugolix included as a preferred oral alternative to injectable GnRH agonists for prostate cancer with lower cardiovascular event risk.
• EMA and ACOG Positions:
• Acknowledge the role of Relugolix-based combinations for non-surgical management of uterine fibroids and endometriosis.

• Storage Temperature: 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity & Light: Store in a dry location, away from excessive moisture and direct light
• Handling Instructions:
• Do not crush or chew tablets
• Keep in blister pack until time of use
• No refrigeration required
• No reconstitution necessary