Introduction
Elagolix is an orally administered, nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist approved by the FDA for the management of moderate to severe pain associated with endometriosis. As the first oral GnRH antagonist in its class, elagolix represents a significant advancement in the treatment of endometriosis-related pain, offering patients an alternative to injectable GnRH agonists and surgical interventions.
Mechanism of Action
Elagolix acts as a competitive antagonist at the GnRH receptor in the pituitary gland. By binding reversibly to these receptors, elagolix inhibits the release of gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), resulting in reduced ovarian hormone production. This leads to decreased circulating levels of estrogen and progesterone, creating a hypoestrogenic state that helps alleviate endometriosis-related pain by reducing the growth and inflammation of endometrial tissue outside the uterus.
Indications
Elagolix is FDA-approved for the management of moderate to severe pain associated with endometriosis. It is specifically indicated for:
- Dysmenorrhea (painful menstruation) associated with endometriosis
- Non-menstrual pelvic pain associated with endometriosis
Dosage and Administration
Standard dosing:- 150 mg once daily for up to 24 months
- 200 mg twice daily for up to 6 months (for women who fail to achieve satisfactory pain control with 150 mg once daily)
- Oral administration with or without food
- Tablets should be swallowed whole with water
- Hepatic impairment: Not recommended in patients with severe hepatic impairment
- Renal impairment: No dosage adjustment necessary for mild to moderate impairment; use with caution in severe renal impairment
- Elderly: Not indicated for use in postmenopausal women
- Pediatrics: Safety and effectiveness not established in pediatric patients
Pharmacokinetics
Absorption: Rapidly absorbed with peak plasma concentrations achieved within 0.5-1.5 hours. Absolute bioavailability is approximately 10% due to first-pass metabolism. Distribution: Volume of distribution is approximately 1,000 L. Protein binding is approximately 80%, primarily to albumin and alpha-1 acid glycoprotein. Metabolism: Primarily metabolized by CYP3A4 with minor contributions from CYP2C8. Elagolix undergoes extensive hepatic metabolism. Elimination: Terminal half-life is approximately 4-6 hours. Excretion is primarily fecal (90.3%) with minor renal elimination (6.6%).Contraindications
- Known hypersensitivity to elagolix or any component of the formulation
- Pregnancy
- Osteoporosis
- Severe hepatic impairment (Child-Pugh Class C)
- Concomitant use with strong CYP3A4 inducers
Warnings and Precautions
Bone loss: Elagolix causes dose-dependent bone loss, which may not be completely reversible. Bone mineral density (BMD) assessment should be considered. Suicidal ideation and mood disorders: Increased risk of suicidal ideation and behavior. Patients should be monitored for new or worsening depression, anxiety, or mood changes. Hepatic transaminase elevations: Periodic monitoring of liver enzymes recommended. Change in menstrual pattern: Expected due to mechanism of action; may result in amenorrhea or irregular bleeding. Hyperlipidemia: May increase LDL and total cholesterol; lipid levels should be monitored.Drug Interactions
Strong CYP3A4 inducers: Contraindicated (e.g., rifampin, carbamazepine, St. John's wort) - significantly decrease elagolix exposure Strong CYP3A4 inhibitors: Use with caution (e.g., ketoconazole, ritonavir) - may increase elagolix exposure Oral P-glycoprotein substrates: May increase concentrations of drugs that are P-gp substrates (e.g., digoxin) Hormonal contraceptives: May reduce efficacy; non-hormonal contraception recommendedAdverse Effects
Most common adverse reactions (≥5%):- Hot flashes (25-50%)
- Headache (15-20%)
- Nausea (10-15%)
- Insomnia (5-10%)
- Amenorrhea (5-10%)
- Anxiety (5-10%)
- Arthralgia (5-10%)
- Depression (5-10%)
- Suicidal ideation and behavior
- Severe hepatic injury
- Significant bone loss
- Severe mood disorders
Monitoring Parameters
- Pain assessment and treatment response
- Bone mineral density (baseline and periodically during treatment)
- Liver function tests (baseline and periodically)
- Lipid profile (baseline and periodically)
- Mood and depression screening
- Pregnancy status (prior to initiation and during treatment)
- Menstrual pattern changes
Patient Education
- Use effective non-hormonal contraception during treatment and for one week after discontinuation
- Report any suicidal thoughts, depression, or mood changes immediately
- Be aware of potential for hot flashes and night sweats
- Understand that menstrual patterns will likely change during treatment
- Maintain adequate calcium and vitamin D intake
- Do not breastfeed while taking elagolix
- Inform all healthcare providers about elagolix use
- Report any signs of liver problems (jaundice, dark urine, abdominal pain)
- Attend all scheduled follow-up appointments for monitoring
References
1. Taylor HS, Giudice LC, Lessey BA, et al. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017;377(1):28-40. 2. Orilissa® (elagolix) [package insert]. North Chicago, IL: AbbVie Inc.; 2020. 3. Surrey E, Taylor HS, Giudice L, et al. Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies. Obstet Gynecol. 2018;132(1):147-160. 4. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 114: Management of Endometriosis. Obstet Gynecol. 2010;116(1):223-236. 5. Archer DF, Stewart EA, Jain RI, et al. Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: a phase 2a proof-of-concept study. Fertil Steril. 2017;108(1):152-160.