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EDITORIAL

Elagolix: A new treatment for pelvic caused by

Two doses of are now FDA approved for treatment of caused by endometriosis. These two doses allow clinicians to opt for gentle (150 mg once daily) or strong (200 mg twice daily) suppression of to manage pelvic pain, as well as the associated effects of low estradiol levels.

Robert L. Barbieri, MD Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston

ndometriosis is the presence The options for treatment of pelvic pain of tissue resembling endome- threshold hypothesis caused by endometriosis: E trial glands and stroma out- The estradiol concentration that 1. strong suppression of estradiol to a side of the uterine cavity. Women causes endometriosis lesions to grow concentration below 20 pg/mL with endometriosis often present or regress varies among women, but 2. gentle suppression of estradiol to a for medical care with at least one a concentration less than 20 pg/mL concentration in the range of 20 to of 3 problems: pelvic pain, infertil- usually causes lesions to regress, 45 pg/mL. ity, and/or an adnexal mass due to and a concentration greater than Strong suppression of estradiol to lev- endometriosis.1 Many clinical obser- 60 pg/mL usually supports lesion els below 20 pg/mL will reliably induce vations demonstrate that endome- growth and maintains lesion viabil- and cause regression of triosis lesions require estrogen to ity.2 Although an estradiol concen- endometriosis lesions, thereby reduc- grow and maintain their viability, tration below 20 pg/mL may cause ing pelvic pain. Strong suppression including that: (1) endometriosis is lesions to regress, it also is associ- of estradiol also will cause moderate uncommon before puberty or after ated with moderate to severe hot to severe hot flashes and accelerated , (2) surgical removal of flashes and accelerated bone loss. bone loss in many women. By con- both results in regression These adverse effects limit the use trast, gentle suppression of circulat- of endometriosis lesions, and (3) of strong suppression of estrogen as ing estradiol to a concentration in the -releasing a long-term treatment strategy. The range of 20 to 45 pg/mL may result (GnRH) analogues cause a hypo‑ estrogen threshold hypothesis pos- in amenorrhea or oligomenorrhea, estrogenic hormonal environment, its that gently suppressing estradiol suppression of the growth of endo- resulting in regression of endometri- to a concentration between 20 and metriosis lesions, a modest reduction osis lesions and improvement in pel- 45 pg/mL may simultaneously cause in pelvic pain, mild hot flashes, and vic pain. Since endometriosis lesions endometriosis lesions to regress, minimal bone loss. require estrogen to maintain their resulting in reduced pelvic pain, min- Recently, the US and Drug viability, suppressing estradiol is a imal bone loss, and few hot flashes.2 Administration (FDA) approved logical approach to hormonal treat- Building on the estrogen thresh- elagolix, an oral GnRH antagonist, for ment of the disease. old hypothesis, clinicians have two treatment of endometriosis.3 Elagolix

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CONTINUED FROM PAGE 10 blocks GnRH receptors in the pitu- itary gland, resulting in reduced pro- Safety information for elagolix3 duction of and follicle stimulating hormone and a • Contraindications: Elagolix should not be prescribed to women who are decrease in sex steroid in currently pregnant or have known or severe hepatic impair- the ovarian follicles, which leads to ment. Elagolix should not be used in women taking cyclosporine or gemfi- a reduction in the production and brozil (organic anion transporting polypeptide inhibitors). • Elagolix may cause dose-dependent bone loss. circulating concentration of estra- • Elagolix reduces menstrual bleeding, which may make it difficult to recog- diol. The FDA approved two doses of nize the occurrence of . Nonhormonal contraceptives should be elagolix: 150 mg once daily for up to utilized during elagolix treatment. 24 months and 200 mg twice daily for • Elagolix may be associated with an increase in reported depressive symp- up to 6 months. Importantly, elagolix toms and changes. at a dose of 150 mg once daily results • Elagolix may be associated with an increase in alanine aminotransferase in a mean circulating estradiol con- more than 3 times the upper limit of the reference range. If elevated function tests are detected, the benefits and risks of continuing elagolix centration of 41 pg/mL, indicating treatment should be evaluated. gentle suppression of ovarian estra- diol production, and 200 mg twice daily results in a mean circulating P<.001). Hot flashes that were severe leuprolide has been one of ovarian estradiol concentration of enough to be classified as adverse the most commonly used hormonal 12 pg/mL, indicating strong suppres- events by study participants were treatments for endometriosis in the sion of ovarian estradiol production.3 reported by 42%, 24%, and 7% of the . A 3-month formula- For clinicians treating women with women in the high-dose, low-dose, tion of depot leuprolide acetate with pelvic pain caused by endometriosis, and groups, respectively. an 11.25-mg injection has resulted these two elagolix regimens permit the was measured at base- in mean circulating estradiol con- individualization of hormonal therapy line and after 6 months of treatment. centrations of 8 pg/mL, indicating to the unique needs of each woman. Lumbar bone density changes were very strong suppression of estradiol -2.61%, -0.32%, and +0.47%, and hip/ production.6 A twice-daily 200-µg Elagolix benefits femoral/neck bone density changes dose of acetate nasal spray and adverse effects were -1.89%, -0.39%, and +0.02% in has resulted in a circulating estra- In one large (Elaris Endo- the high-dose, low-dose, and placebo diol concentration of approximately metriosis I), 872 women were ran- groups, respectively. 28 pg/mL, indicating gentle suppres- domly assigned to treatment with one Another large clinical trial of sion of estradiol production.7 of two doses of elagolix (200 mg twice elagolix for treatment of pelvic pain At current prices, elagolix treat- daily [high-dose group] or 150 mg caused by endometriosis (Elaris ment is substantially less expensive once daily [low-dose group]) or pla- II) involving 817 women produced than treatment with leuprolide or cebo.4 After 3 months of treatment, results that were similar to those nafarelin. In addition, many women a clinically meaningful reduction in reported in Elaris I.4 The elagolix in my practice prefer to use an oral pain was reported continuation studies, Elaris III and medication over an intramuscular by 76%, 46%, and 20% of women in IV, demonstrated and safety injection or a nasal spray medica- the high-dose, low-dose, and pla- of elagolix through 12 months of tion. It is likely that clinicians and cebo groups, respectively (P<.001 for treatment.5 patients will evolve to prioritize and comparisons of elagolix to placebo). favor elagolix therapy over depot In addition, at 3 months, a clinically Depot leuprolide acetate leuprolide or nafarelin treatment. meaningful reduction in nonmen- and nafarelin acetate strual pain or decreased or stable use Depot leuprolide acetate and nafare- 5 options for using elagolix of rescue analgesics was reported by lin acetate are GnRH analogues There are many potential options 55%, 50%, and 37% of women in the approved by the FDA more than for using elagolix in the treatment of high-dose, low-dose, and placebo 25 years ago for treatment of pel- pelvic pain caused by endometriosis. groups, respectively (low-dose vs pla- vic pain caused by endometriosis. Option 1. Prescribe elagolix 200 mg cebo, P<.01; high-dose vs placebo, Over the past two decades, depot twice daily for 6 months to achieve

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5 options for using elagolix to treat endometriosis-associated pelvic pain

Option Dysmenorrhea pain Hot flashes Bone loss elagolix 200 mg twice daily strong improvement increase greater 1 for 6 monthsa

2 elagolix 150 mg once daily modest improvement fewer minimal for up to 24 monthsa

elagolix 200 mg twice daily strong improvement fewer minimal 3 for 3 months, switch to elagolix 150 mg once daily for up to 24 monthsb 4 alternating regimen of elagolix 200 mg twice moderate improvement [not clear] [not clear] daily on even days of the month and one pill daily on odd days of the monthb elagolix 200 mg twice daily and initiate add- strong improvement fewer minimal 5 back therapy with norethindrone acetate at a dose of 5 mg once dailyc

aFDA-approved treatment option. bTreatment option is not FDA approved. cBased on FDA approved combination leuprolide- norethindrone acetate regimen.

strong suppression of estradiol and which is likely to maintain decreased mitigate the bone loss that occurs marked improvement in dysmenor- pain symptoms with minimal long- with strong suppression of estradiol rhea, although at the cost of more term bone loss and fewer hot flashes. and reduces the frequency of moder- hot flashes and greater bone loss. Option 4. Prescribe an alternating ate to severe hot flashes. Option 2. Prescribe elagolix 150 mg regimen of elagolix 200 mg twice Option 5 is based on extrapo- once daily for up to 24 months to daily on even days of the month (two lation from high-quality studies achieve gentle suppression of estra- pills daily is an even number of pills) of leuprolide acetate depot plus nor- diol and modest improvement in and one pill daily on odd days of the ethindrone acetate add-back.8 The dysmenorrhea with fewer hot flashes month (1 pill daily is an odd number combination regimen is approved and minimal bone loss. of pills). This regimen should pro- by the FDA.3 Options 1 and 2 have been duce a mean estradiol concentration studied in high quality clinical trials between 12 and 41 pg/mL, resulting Elagolix availability increases involving more than 1,500 women in moderate rather than strong or treatment choices for women and are approved by the FDA. gentle suppression of estradiol. Pelvic pain caused by endometriosis Option 3. Initiate treatment with Options 3 and 4 are based on is common, affecting approximately elagolix 200 mg twice daily for 3 extrapolation using our knowledge 8% of women of reproductive age.9 months, immediately accruing the about the hormonal treatment of Endometriosis is a vexing disease benefits of strong suppression of endometriosis and are not regimens because diagnosis is often delayed estradiol, and then switch to elago- approved by the FDA. many years after the onset of symp- lix 150 mg once daily for up to Option 5. Prescribe elagolix 200 mg toms, causing great frustration 24 months to achieve continuing pain twice daily and initiate add-back among patients.10 Some effective control with fewer adverse effects. therapy with norethindrone acetate hormonal treatment options, includ- This regimen combines strong ini- 5 mg once daily. Substantial evidence ing and depot leuprolide, tial suppression of estradiol, which supports the combination of a GnRH are poorly tolerated by patients will result in marked improvement analogue that strongly suppresses because of adverse effects, including in dysmenorrhea, along with long- estradiol production with norethin- (danazol), hot flashes, term gentle suppression of estradiol, drone acetate add-back, which helps and bone loss (depot leuprolide).

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Combination oral contraceptives that dosing can be tailored for each gynecologists are the clinicians best used in a continuous or cyclic fashion patient to achieve reduction in pain trained to care for these women, and often result in inadequate improve- while minimizing unwanted adverse patients trust that we will effectively ment in pelvic pain.11 The synthesis effects such as hot flashes and bone treat their problem. of an orally active, small-molecule loss. In Elaris Endometriosis I, fewer GnRH antagonist is an innovative than 10% of women discontinued advance in endocrine pharmacol- elagolix due to adverse effects.4 ogy. The Elaris Endometriosis clini- Elagolix is also less expensive than cal trials have demonstrated that depot leuprolide and nafarelin. [email protected] elagolix is effective in the treatment Millions of women in the United of pelvic pain caused by endometrio- States have pelvic pain caused Dr. Barbieri reports no financial rela- sis.4,5 A great advantage of elagolix is by endometriosis. Obstetrician- tionships relevant to this article.

References 1. Falcone T, Flyckt R. Clinical management of endometriosis: results from two extension studies. Back Study Group. Obstet Gynecol. 1998;91:16-24. endometriosis. Obstet Gynecol. 2018;131:557-571. Obstet Gynecol. 2018;132:147-160. 9. Missmer SA, Hankinson SE, Spiegelman D, et 2. Barbieri RL. Hormonal treatment of endo- 6. Lupron Depot [package insert]. North Chicago, IL: al. The incidence of laparoscopically-confirmed metriosis: the estrogen threshold hypothesis. Am : 2012. endometriosis by demographic, anthropomorphic J Obstet Gynecol. 1992;166:740-745. 7. Henzl MR, Corson SL, Moghissi K, et al. and lifestyle factors. Am J Epidemiol. 2004;160: 3. Orlissa [package insert]. North Chicago, IL: Administration of nasal nafarelin as compared 784-796. AbbVie Inc; 2018. with oral danazol for endometriosis. a multicenter 10. Barbieri RL. Why are there delays in the diagnosis 4. Taylor HS, Giudice LC, Lessey BA, et al. Treatment of double-blind comparative clinical trial. N Engl J of endometriosis? OBG Manag. 2017;29:8,10-11,16. endometriosis-associated pain with elagolix, an oral Med. 1988;318:485-489. 11. Jensen JT, Schlaff W, Gordon K. Use of combined GnRH antagonist. N Engl J Med. 2017; 377: 28-40. 8. Hornstein MD, Surrey ES, Weisberg GW, et al. hormonal contraceptives for the treatment of 5. Surrey E, Taylor HS, Giudice L, et al. Long- Leuprolide acetate depot and hormonal add-back endometriosis-related pain: a systematic review term outcomes of elagolix in women with in endometriosis: a 12-month study. Lupron Add- of the evidence. Fertil Steril. 2018;110:137-152.

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