Introduction
Oriahnn (elagolix/estradiol/norethindrone acetate) is a novel oral medication approved by the FDA in 2020 for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. It represents the first FDA-approved oral medication specifically indicated for this condition. Oriahnn combines a gonadotropin-releasing hormone (GnRH) receptor antagonist with hormone replacement therapy to provide symptomatic relief while mitigating hypoestrogenic effects.
Mechanism of Action
Oriahnn contains three active components: 1. Elagolix: A competitive GnRH receptor antagonist that binds to pituitary GnRH receptors, reducing the release of gonadotropins (LH and FSH), which subsequently suppresses ovarian estrogen production 2. Estradiol: A bioidentical estrogen that provides hormone replacement to reduce vasomotor symptoms and bone loss associated with estrogen suppression 3. Norethindrone acetate: A progestin that provides endometrial protection against unopposed estrogen stimulation
This combination allows for targeted suppression of estrogen-driven fibroid growth while providing hormone replacement to minimize hypoestrogenic adverse effects.
Indications
- Management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women
- Treatment duration should be limited to 24 months due to the risk of irreversible bone loss
Dosage and Administration
Standard dosing: One capsule taken orally twice daily (approximately every 12 hours) Administration: Can be taken with or without food Treatment duration: Maximum of 24 months Missed dose: Take as soon as remembered unless it's almost time for the next dose Special populations:- Renal impairment: No dosage adjustment necessary for mild to moderate impairment; not studied in severe impairment
- Hepatic impairment: Contraindicated in patients with known liver impairment
- Geriatric: Not indicated for use in postmenopausal women
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption:- Elagolix: Tmax ~1.5 hours; high-fat meal increases AUC by 30% and Cmax by 22%
- Estradiol: Tmax ~6-8 hours; administration with food increases AUC by 18-24%
- Norethindrone acetate: Rapidly metabolized to norethindrone; Tmax ~1.5-2 hours
- Elagolix: 80% plasma protein bound; Vd ~1,000 L
- Estradiol: Highly protein bound (98%), primarily to sex hormone-binding globulin
- Norethindrone: Highly protein bound (96%), primarily to albumin
- Elagolix: Primarily metabolized by CYP3A4; minor contributions from CYP2C8
- Estradiol: Extensive hepatic metabolism via hydroxylation, conjugation, and oxidation
- Norethindrone: Extensive hepatic metabolism via reduction, hydroxylation, and conjugation
- Elagolix: Feces (90%) and urine (10%); terminal half-life ~4-6 hours
- Estradiol: Primarily renal excretion; terminal half-life ~12-20 hours
- Norethindrone: Renal and fecal excretion; terminal half-life ~8-10 hours
Contraindications
- Known hepatic impairment or disease
- Current or history of thromboembolic disorders
- Known osteoporosis
- Undiagnosed abnormal uterine bleeding
- Known or suspected pregnancy
- Current or history of breast cancer or other hormone-sensitive malignancies
- Hypersensitivity to any component of Oriahnn
- Concomitant use with strong OATP1B1 inhibitors
Warnings and Precautions
Bone loss: Oriahnn causes dose-dependent bone mineral density (BMD) loss, which may not be completely reversible. Limit duration to 24 months. Thromboembolic disorders: Increased risk of thrombotic and thromboembolic events, including pulmonary embolism, stroke, and myocardial infarction. Hormone-sensitive malignancies: The estradiol component may increase risk of malignancies in women with known or suspected estrogen-dependent neoplasia. Gallbladder disease: Estrogen and progestin therapy may increase risk of gallbladder disease. Hepatic impairment and transaminase elevations: Contraindicated in women with liver impairment. Monitor liver enzymes periodically. Hypertension: Monitor blood pressure regularly. Lipid metabolism: May adversely affect lipid parameters. Mood disorders and depression: New onset or exacerbation of existing mood disorders may occur. Uterine fibroid prolapse or expulsion: May occur in women with submucosal fibroids.Drug Interactions
Strong CYP3A4 inducers (e.g., carbamazepine, rifampin): May decrease elagolix concentrations; avoid concomitant use Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): May increase elagolix concentrations; avoid concomitant use OATP1B1 inhibitors (e.g., cyclosporine, gemfibrozil): May increase elagolix concentrations; contraindicated Hormonal contraceptives: Additional hormones may increase risk of adverse events; use alternative non-hormonal contraception Substrates of CYP enzymes: Elagolix may induce CYP3A and inhibit CYP2C8; monitor drugs metabolized by these enzymesAdverse Effects
Most common adverse reactions (≥3%):- Hot flush (40%)
- Headache (15%)
- Fatigue (7%)
- Nausea (6%)
- Alopecia (5%)
- Night sweats (5%)
- Amenorrhea (4%)
- Depression (4%)
- Hyperhidrosis (4%)
- Thromboembolic events
- Hepatic transaminase elevations
- Suicidal ideation and behavior
- Unintended pregnancy
- Bone loss
Monitoring Parameters
- Bone mineral density: Assess at baseline and periodically during treatment
- Liver enzymes: Monitor at baseline and periodically
- Lipid profile: Assess at baseline and periodically
- Blood pressure: Monitor regularly
- Pregnancy status: Rule out pregnancy before initiation and monthly during treatment
- Mental health status: Monitor for mood changes and depression
- Heavy menstrual bleeding: Assess clinical response
- Hemoglobin: Monitor in patients with anemia
Patient Education
- Take medication exactly as prescribed, approximately every 12 hours
- Use effective non-hormonal contraception during treatment (Oriahnn reduces efficacy of hormonal contraceptives)
- Report immediately any signs of blood clots: leg pain, chest pain, shortness of breath, vision changes, or severe headache
- Be aware of potential mood changes, depression, or suicidal thoughts
- Understand that treatment is limited to 24 months due to bone loss risk
- Regular monitoring of bone density and liver function will be necessary
- Report any pregnancy or suspected pregnancy immediately
- Be aware that menstrual bleeding patterns will change, potentially to amenorrhea
- Maintain adequate calcium and vitamin D intake
- Report any signs of liver problems: jaundice, dark urine, fatigue, or abdominal pain
References
1. FDA Prescribing Information: Oriahnn (elagolix, estradiol, and norethindrone acetate). 2020. 2. Al-Hendy A, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384(7):630-642. 3. Stewart EA, et al. Elagolix alone or with add-back therapy in women with heavy menstrual bleeding and uterine leiomyomas: a randomized controlled trial. Obstet Gynecol. 2020;136(5):1005-1016. 4. Archer DF, et al. Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: the Elaris UF-1 and UF-2 studies. Obstet Gynecol. 2020;136(5):1005-1016. 5. Simon JA, et al. Safety profile of elagolix in women with uterine fibroids: results from two phase 3 trials. Fertil Steril. 2020;114(3):e10-e11.