By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first drug for the treatment of moderate to severe endometriosis pain. Elagolix is a nonpeptide, orally active, gonadotropin-releasing hormone (GnRH) receptor antagonist. It received priority review and will be marketed as Orilissa.
Elagolix is indicated for the management of moderate to severe pain associated with endometriosis.1
For patients with normal or mild liver impairment, the dose is 150 mg daily up to 24 months or 200 mg twice daily up to six months.1 For patients with moderate liver impairment, the dose is 150 mg daily up to six months. Elagolix is contraindicated in patients with severe liver impairment, pregnancy, women with osteoporosis, or concomitant use of an organic anion-transporting peptide inhibitor (e.g., cyclosporine, gemfibrozil). Elagolix is available as 150 mg and 200 mg tablets.
Elagolix is the first drug developed to manage moderate to severe endometriosis pain with the added benefit of oral administration. It causes less estrogen suppression than GnRH receptor agonists commonly used for endometriosis.
Elagolix causes a dose-dependent reduction in bone mineral density (BMD) that may not be completely reversible, particularly at the higher dose.1 Twenty-one percent of subjects on the 200 mg dose demonstrated greater than 8% BMD decrease in lumbar spine, total hip, or femoral neck at any time over a 12-month treatment period compared to 8% with the same magnitude of decrease on the 150 mg dose.1 The drug alters menstrual bleeding and may reduce a woman’s ability to recognize a pregnancy. Suicidal ideation and mood disorders have been reported. Elagolix reduces the estrogen effect of contraceptives; therefore, a nonhormonal contraceptive is recommended during and up to one week after discontinuation of treatment.
Elagolix suppresses sex hormone secretion in a rapid and reversible manner by competitive inhibition of the GnRH receptor.1 FDA approval was based on two similar double-blind, randomized, placebo-controlled, six-month, Phase III studies that included women subjects with moderate to severe pain associated with surgically diagnosed endometriosis.1,2 In study 1, researchers randomized 1,689 subjects to elagolix 150 mg daily, 200 mg twice daily, or placebo. The coprimary efficacy endpoints were the proportion of subjects whose dysmenorrhea responded to treatment and the proportion whose pelvic pain (not related to menses) responded to treatment at month three. These were based on subjects’ self-report assessment on a 4-point scale. Response was defined as a reduction in dysmenorrhea pain and nonmenstrual pelvic pain with no increase in analgesic use. The clinically meaningful changes from baseline compared to placebo for studies 1 and 2 were set at -0.81 and -0.85 for dysmenorrhea pain, and nonmenstrual pain at -0.36 and -0.43, respectively.
Response rates were 46% for the 150 mg dose regimen, 76% for the 200 mg regimen, and 20% for placebo in study 1. Correspondingly, the results were 43%, 72%, and 23% for study 2. The frequency of responders for nonmenstrual pain was 50% for the 150 mg regimen, 55-58% for the 200 mg regimen, and 36-37% for placebo. Generally, benefits were sustained at six months and up to 12 months in subjects who continued in two 12-month extension studies.3
The most common (> 20%) adverse reactions were hot flashes or night sweats (24% for the lower-dose regimen and 46% for the high-dose regimen vs. 9% for placebo).1 These adverse reactions continued into the extension studies, with a frequency ranging from 30-55% and were the primary reason for discontinuation of treatment.1,3 The most common reason for discontinuation in the extension studies was decrease in BMD > 8% from baseline per study protocol. Dose-dependent elevation of liver enzymes (three times the upper limit of normal) and plasma lipids were reported. No adverse endometrial findings were reported and generally were associated with a dose-dependent decrease in endometrial thickness.1
Endometriosis is a chronic, estrogen-dependent disorder characterized by chronic pain and infertility.4 It affects approximately 6-19% of women in reproductive age. Some medical therapies include nonsteroidal anti-inflammatory drugs, combined hormonal contraceptives, progestogens, danazol, and GnRH agonists.5 Elagolix offers an alternative to GnRH agonists. Because of its mechanism of action, GnRH agonists such as leuprolide, buserelin, goserelin, and nafarelin cause an initial flare and may result in worsening of symptoms for the first four to six weeks of treatment, with profound hypoestrogenic effects.6 Often, add-back therapy (e.g., estrogen, progestin, bisphosphonates) is used to reduce BMD loss and provide symptomatic relief.4 Elagolix onsets faster, eliminates the “flare” phase, results in a less profound hypoestrogenic effect, and does not usually require add-back therapy.
The frequency of hot flashes is similar to that of a GnRH agonist plus add-back therapy.3 BMD reduction at 12 months was similar with the 150 mg dose of elagolix compared to that reported for leuprolide 3.75 mg with norethindrone acetate 5 mg.3,7 Elagolix offers the convenience of oral administration compared to intranasal or injection (e.g., subcutaneous) for GnRH receptor agonists. The drug will cost $844.87 for a 28-day supply or $10,983.31 for a 52-week supply.
- Orilissa Prescribing Information. AbbVie Inc., July 2018. Available at: . Accessed Sept. 11, 2018.
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med 2017;377:28-40.
- 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;132:147-160.
- [No authors listed]. Practice bulletin no. 114: Management of endometriosis. Obstet Gynecol 2010;116:223-236.
- The Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: A committee opinion. Fertil Steril 2014;101:927-935.
- Lindsay SF, Luciano DE, Luciano AA. Emerging therapy for endometriosis. Expert Opin Emerg Drugs 2015;20:449-461.
- Lupron Depot Prescribing Information. AbbVie Inc., April 2018. Available at: . Accessed Sept. 11, 2018.