Elagolix

631.595

631.59

5B2546MB5Z

DTXSID40232348

C153373

H - Systemic hormonal preparations, excl. sex hormones and insulins

99.2

7.20

1.4±0.1 g/cm3

728.6±70.0 °C at 760 mmHg

394.5±35.7 °C

1.567

<1 mg/mL

P201, P202, P281, P308+P313, P405, P501

H361

|Danger|H304 (88%): May be fatal if swallowed and enters airways [Danger Aspiration hazard]|P201, P202, P264, P280, P281, P301+P310, P305+P351+P338, P308+P313, P331, P337+P313, P405, and P501|Aggregated GHS information provided by 50 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H360 (50%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed. Common adverse reactions of elagolix include hot flush, headache, nausea, insomnia, mood alterations, amenorrhea, depression, anxiety, arthralgia, bone loss, changes in menstrual bleeding patterns, suicidal ideation and behavior, exacerbation of existing mood disorders, and/or hepatic transaminase elevations. The recommended duration of use for elagolix is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months.

Elagolix therapy has been associated with serum enzyme elevations in a small proportion of patients, rates of ALT elevations above 3 times the upper limit of normal being 0.2% with 150 mg once daily and 1.1% with 200 mg twice daily. The elevations, however, are generally mild and self-limited, resolving even without dose adjustment. Occasional patients require drug discontinuation because of serum enzyme elevations, but there were no instances of liver injury with jaundice or clinically apparent acute liver injury in the preregistration-controlled trials. Since its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to elagolix.

The percentage bound to human plasma proteins for elagolix has been documented as 80%.

Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis.|FDA Label|Treatment of endometriosis|Treatment of uterine leiomyoma

Elagolix is an oral, nonsteroidal gonadotropin releasing hormone (GnRH) antagonist that decreases estrogen production and is used to treat painful forms of endometriosis in women. Elagolix therapy is associated with a low rate of serum enzyme elevations during therapy and has yet to be linked to instances of clinically apparent liver injury.

Obstetrical and Gynecological Agents

During a three menstrual cycle study in healthy women, an elagolix 150 mg once daily regimen and a 200 mg twice daily regimen resulted in an ovulation rate of about 50% and 32%, respectively. In Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for the 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen. Furthermore, the effect of elagolix on the QTc interval was investigated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects administered a single dose of 1200 mg was seventeen times higher than the concentration in subjects given elagolix 200 mg twice daily. Nevertheless, there was no clinically relevant prolongation of the QTc interval.

The Tmax of elagolix is reported as being 1.0 hours. The effect of a high-fat meal (relative to fasting) can result in a reduction of the AUC and Cmax by as much as 24% and 36%, respectively.|The primary route of elimination of elagolix is via hepatic metabolism.|The apparent volume of distribution at steady state (Vdss/F) of elagolix is reported to be 1674 for a 150 mg daily regimen and 881 for a 200 mg twice daily regimen.|The oral clearance (CL/F) of elagolix is 123 L/hr for a 150 mg once daily regimen and 144 L/hr for a 200 mg twice daily regimen.

Elagolix is predominantly metabolized by the CYP3A family of isoenzymes despite participating in minor metabolic pathways with the CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) enzymes as well. The primary metabolite of elagolix, referred to as NBI-61962 (R-(+)-4-{2-[5-(2-fluoro-3-hydroxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino}-butyrate), is not believed to possess any significant biologic activity due to its low plasma exposure and an observed potency that is exceptionally less than the parent elagolix compound (Ki value of 3.5 compared to 0.9 nM).

The terminal phase elimination half-life of elagolix is recorded as being 4 to 6 hours.

Endometriosis develops when tissue that is similar to the kind that is normally located in the uterus starts to grow outside of the uterus. Such growth leads to various symptoms like pain during periods, pelvic pain between periods, and pain during sexual intercourse. The growths themselves are referred to as lesions and frequently develop on the ovaries, fallopian tubes, and other areas around the uterus, including the bowel or bladder. The growth of these lesions is dependent upon the estrogen hormone. Elagolix is an orally-administered, nonpeptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

elagolix

Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients