ORILISSA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ORILISSA (ORILISSA).
Elagolix is a nonpeptide, orally active gonadotropin-releasing hormone (GnRH) receptor antagonist that competitively inhibits GnRH binding to pituitary GnRH receptors, resulting in suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, thereby reducing ovarian sex hormone production.
| Metabolism | Elagolix is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. |
| Excretion | Approximately 86% of the dose is excreted in feces (as unchanged drug and metabolites) and about 20% in urine (primarily as metabolites). Renal elimination of unchanged drug is <1%. |
| Half-life | Terminal elimination half-life is approximately 6.5 hours (range 4–9 hours) in healthy subjects; clinical effect in endometriosis requires daily dosing. |
| Protein binding | Approximately 86% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is about 40 L (approximately 0.6 L/kg), indicating distribution into total body water. |
| Bioavailability | Oral bioavailability is approximately 35% (range 30–40%) due to first-pass metabolism. |
| Onset of Action | Oral: Reduction in estradiol levels occurs within 4–8 hours; clinical improvement in pain may take several weeks. |
| Duration of Action | Suppression of estradiol lasts for approximately 24 hours with once-daily dosing; therapeutic effects on endometriosis pain are sustained with continuous use. |
100 mg orally once daily for endometriosis; 200 mg orally twice daily for uterine fibroids.
| Dosage form | TABLET |
| Renal impairment | No adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe impairment (CrCl <30 mL/min) or dialysis. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose to 100 mg once daily for endometriosis (no data for fibroids); Child-Pugh C: contraindicated. |
| Pediatric use | Not approved for use in pediatric patients. |
| Geriatric use | Not indicated for use in elderly patients; no specific dose adjustments established due to lack of studies. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ORILISSA (ORILISSA).
| Breastfeeding | Excreted in breast milk; M/P ratio unknown. Discontinue breastfeeding or discontinue drug due to potential adverse effects on breastfed infant, especially effects on estradiol levels. |
| Teratogenic Risk | Pregnancy category X. First trimester exposure associated with increased risk of ectopic pregnancy and spontaneous abortion. Second and third trimester exposure may cause fetal harm due to hormonal disruption and potential effects on reproductive tract development. Contraindicated in pregnancy. |
| Fetal Monitoring |
■ FDA Black Box Warning
Not approved for use in pregnancy; pregnancy must be excluded before starting treatment, and patients should use effective non-hormonal contraception during treatment and for a period after discontinuation.
| Serious Effects |
["Known pregnancy","Active osteoporosis or history of fragility fracture","Severe hepatic impairment (Child-Pugh Class C)","Use of strong CYP3A4 inhibitors or inducers with specific dose adjustments"]
| Precautions | ["Bone loss: dose- and duration-dependent decrease in bone mineral density (BMD); not recommended for use beyond 24 months.","Contraception: pregnancy must be excluded; non-hormonal contraception required.","Hepatic impairment: not recommended in severe impairment; reduce dose in moderate impairment.","Depression and mood changes: monitor for new or worsening symptoms.","Altered menstrual bleeding: may reduce intensity or stop menses; breakthrough bleeding possible."] |
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| Perform pregnancy test prior to initiation and monthly during therapy. Confirm non-pregnant status. Monitor for significant uterine bleeding; rule out pregnancy if amenorrhea does not occur. Assess bone mineral density via DXA scan after 12 months of use. |
| Fertility Effects | Reversible suppression of ovulation. Return to estradiol levels consistent with follicular phase occurs within 1 month of discontinuation. Pregnancies can occur after cessation; advise effective non-hormonal contraception during therapy. |