Orili

FDA-Approved Indications:

• Moderate to Severe Pain Associated with Endometriosis:
• In premenopausal women to reduce pelvic pain, dysmenorrhea, and non-menstrual pelvic pain.
• Heavy Menstrual Bleeding Associated with Uterine Fibroids:
• In combination with estradiol and norethindrone acetate in premenopausal women.

Off-label/Clinically Accepted Uses:

• Assisted Reproductive Technologies (under study):
• Investigational use in suppressing premature luteinizing hormone surges during controlled ovarian hyperstimulation cycles (not currently approved).

Endometriosis-Associated Pain:

• 150 mg once daily:
• For up to 24 months in women without moderate-to-severe hepatic impairment and not at risk of bone loss.
• 200 mg twice daily:
• For up to 6 months in women with moderate pain and higher symptom burden, limited due to higher risk of hypoestrogenic effects and bone loss.

Uterine Fibroids (with estradiol/norethindrone acetate):

• Elagolix 300 mg twice daily + estradiol 1 mg + norethindrone acetate 0.5 mg once daily:
• Maximum duration: 24 months.

Pediatrics:

• Safety and efficacy not established; not recommended.

Elderly:

• Not indicated for use in postmenopausal women.

Renal Impairment:

• No dose adjustment required in mild to moderate renal impairment.
• Use not recommended in severe renal impairment without specialist supervision.

Hepatic Impairment:

• Mild impairment: No adjustment needed.
• Moderate impairment: Use only 150 mg once daily for a maximum of 6 months.
• Severe hepatic impairment: Contraindicated.

Route:

• Oral administration, with or without food.

Elagolix sodium is an orally active, non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist. It competitively binds to and inhibits pituitary GnRH receptors, leading to a dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This results in decreased ovarian estradiol and progesterone production. The hypoestrogenic state reduces estrogen-dependent symptoms such as dysmenorrhea, dyspareunia, and pelvic pain in endometriosis, and minimizes uterine bleeding in fibroid-related menorrhagia. Unlike GnRH agonists, elagolix does not cause an initial hormone flare.

• Absorption:
• Rapid absorption; peak plasma concentration (Cmax) achieved in ~1 hour
• Absolute oral bioavailability: ~46%
• Distribution:
• Volume of distribution: ~167 L
• Plasma protein binding: ~80% (primarily to albumin)
• Metabolism:
• Primarily metabolized by CYP3A enzymes
• Minor contribution from CYP2D6 and CYP2C enzymes
• Glucuronidation also involved via UGT1A3
• Elimination:
• Terminal half-life:
• ~4–6 hours (150 mg once daily)
• ~6–8 hours (200–300 mg doses)
• Excreted mainly in feces (~90%) and urine (~3%)
• Steady State:
• Achieved within 2 days of dosing
• Minimal accumulation with repeated doses

• Pregnancy:
• Contraindicated in pregnancy due to potential fetal harm from hormonal suppression.
• Elagolix may increase risk of early pregnancy loss. Use reliable contraception during treatment and for at least 1 week after discontinuation.
• Lactation:
• Unknown if elagolix is excreted in human milk.
• Because of the potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during therapy.
• General:
• Pregnancy testing recommended before initiating therapy.

• Primary Class: GnRH Receptor Antagonist
• Subclass: Non-peptide, orally active hormonal modulator

• Known hypersensitivity to elagolix or any component of the formulation
• Pregnancy
• Known osteoporosis
• Severe hepatic impairment
• Concomitant use with strong CYP3A inhibitors (e.g., ketoconazole) in patients with hepatic impairment
• Use in postmenopausal women

• Bone Mineral Density Loss:
• Elagolix causes dose- and duration-dependent decreases in BMD; may not be completely reversible.
• Limit use duration based on dose and patient risk profile.
• Consider bone density monitoring for long-term use.
• Hepatic Function Monitoring:
• Use cautiously in mild/moderate hepatic impairment; contraindicated in severe cases.
• Mood Disorders:
• Depression, mood swings, and suicidal ideation reported; monitor closely in patients with psychiatric history.
• Menstrual Suppression:
• Amenorrhea is common; rule out pregnancy in case of prolonged absence of menses.
• Lipid Changes:
• May cause elevations in LDL and total cholesterol, especially with higher doses.
• Reduced Hormonal Contraceptive Effectiveness:
• Avoid combination hormonal contraceptives; use non-hormonal methods.

Common (≥5%):

• Reproductive System: Amenorrhea, dysmenorrhea relief, hot flushes, night sweats
• CNS: Headache, insomnia, mood changes, anxiety
• Musculoskeletal: Arthralgia, decreased bone density
• GI: Nausea
• General: Fatigue, irritability

Serious or Rare:

• Suicidal ideation or behavior
• Severe hepatic enzyme elevations
• Osteoporosis or bone fractures (long-term use)
• Menorrhagia rebound after discontinuation

Onset & Severity:

• Most side effects are dose-dependent and relate to hypoestrogenism
• Symptoms usually emerge within weeks of starting treatment

• Strong CYP3A Inhibitors (e.g., ketoconazole, itraconazole):
• May increase elagolix levels and risk of adverse effects. Contraindicated with hepatic impairment.
• OATP1B1 Inhibitors (e.g., cyclosporine, gemfibrozil):
• May significantly increase elagolix plasma concentrations.
• Hormonal Contraceptives:
• Combination hormonal contraceptives may reduce elagolix efficacy and vice versa. Use non-hormonal contraception.
• Digoxin:
• Elagolix may increase digoxin levels via P-gp inhibition. Monitor serum digoxin concentrations.

Enzyme Systems Involved:

• CYP3A4 (major)
• Minor: CYP2D6, CYP2C8
• Substrate of P-gp and OATP1B1

• Recent Guidelines:
• Recognized in updated gynecological guidelines as an effective non-surgical option for endometriosis-related pain and fibroid-related bleeding.
• Labeling Updates (FDA):
• Reinforced limitations on duration of use based on dose and hepatic function.
• Additional post-marketing data on bone density and psychiatric effects included.
• Combination Therapy Approvals:
• FDA approved elagolix with estradiol/norethindrone acetate for fibroid-related bleeding.

• Temperature:
• Store at 20°C to 25°C (68°F to 77°F)
• Excursions permitted between 15°C and 30°C (59°F and 86°F)
• Humidity & Light Protection:
• Keep in original container; protect from moisture
• No special light protection required
• Handling Precautions:
• Keep out of reach of children
• Do not use past expiration date
• No refrigeration or reconstitution necessary