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 Food and Drug Administration (FDA) has approved the first oral treatment for heavy menstrual bleeding caused by uterine fibroids. This combination product contains elagolix (a nonpeptide gonadotropin-releasing hormone antagonist), estradiol, and a progestin, norethindrone acetate. Estrogen is added to attenuate the hypoestrogenic effects (e.g., decreased bone mineral density, hot flushes) of elagolix. Norethindrone acetate is added to protect the uterus from unopposed estrogen. Elagolix was approved in 2018 for the management of moderate to severe pain associated with endometriosis. Elagolix, estrogen, and norethindrone acetate (elagolix-EN) is marketed as Oriahnn.

INDICATIONS

Elagolix-EN should be prescribed to manage heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.1

DOSAGE

The recommended dose is one capsule in the morning and one in the evening, starting within seven days from the onset of menses.1 The morning capsule contains elagolix 300 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg. The evening capsule contains elagolix 300 mg. The use of elagolix-EN should be limited to 24 months because of potential irreversible continued bone loss.1 Elagolix is available as weekly blister packs, with seven morning capsules and seven evening capsules.

POTENTIAL ADVANTAGES

Elagolix-EN is the first FDA-approved, non-surgical treatment specifically for this indication.2

POTENTIAL DISADVANTAGES

Estrogen and progestin combinations increase the risk of thrombotic or thromboembolic disorders and are contraindicated in women with current, a history of, or at increased risk for these events.1 This includes smokers, women with uncontrolled hypertension, and women older than age 35 years. Elagolix-EN also is contraindicated in pregnancy, osteoporosis, current or history of breast cancer, known hepatic impairment or disease, or concomitant use of organic anion transporting polypeptide inhibitors.1 Increases in total cholesterol, low-density lipoprotein, triglycerides, and apolipoprotein can occur with greater changes in those with higher baseline levels.1 Depression and related symptoms were reported in 3% of elagolix-EN-treated subjects vs. 1% in placebo-treated subjects. Fractures were observed in 1.5% of elagolix-EN-treated subjects vs. 0.5% for the placebo group.1 Seventy-one percent of fractures occurred in the post-treatment follow-up period. The most common adverse reaction is hot flush (22% vs. 9% for placebo). Elagolix-EN contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions in certain susceptible patients (e.g., those with aspirin hypersensitivity).1

COMMENTS

The efficacy of elagolix-EN was assessed in two randomized, double-blind, placebo-controlled, six-month studies of subjects with heavy menstrual bleeding associated with uterine fibroids (study 1 and study 2).1,3 Heavy uterine bleeding was defined as at least two menstrual cycles with greater than 80 mL of menstrual blood loss (MBL). Sixty-eight percent of subjects were African American, a median age of 43 years, and reported a mean MBL of 240 mL/cycle. Subjects were randomized to elagolix-EN (study 1, n = 206; study 2, n = 189) or placebo (study 1, n = 102; study 2, n = 94). The primary endpoint was achievement of < 80 mL MBL at the final months or ≥ 50% reduction in MBL volume from baseline.

In study 1, 68.5% were responders compared to 8.7% for placebo. Responders were 76.5% and 10.5%, respectively, in study 2. Difference was observed in month 1 (mean MBL reduction vs. placebo of 120 mL), peaked by month 2, and maintained through the six-month study. Nearly 60% of subjects experienced no bleeding compared to 4% to 5% for the placebo-treated group (mean reduction vs. placebo at six months of approximately 210 mL). Fifty percent to 62% of subjects with baseline Hgb ≤ 10.5 g/dL reported a > 2 g/dL increase compared to 21% and 16%, respectively, for placebo-treated subjects.

CLINICAL IMPLICATIONS

Uterine fibroids are a common, benign pelvic tumor in women (age 35 to 49 years) that can cause heavy menstrual bleeding, pain, bowel and bladder problems, and infertility.2 African American women experience symptoms more often, and those symptoms often are more severe.4,5 In addition, Hispanic women report significant symptom severity.5 The primary treatment option is surgery (i.e., hysterectomy). Approximately 70% of women diagnosed without a hysterectomy used pharmacologic treatment.5 Overall, relief from heavy bleeding was cited as the most important treatment goal. Currently, there are no FDA-approved non-surgical options. Based on a large administration claims database, most U.S. women took short-acting reversible contraceptive steroids as first-line treatment for heavy menstrual bleeding.6 However, only 14% continued their initial medication, while the rest either switched from or discontinued the initial medication. Elagolix-EN is the first FDA-approved pharmacologic option that effectively reduces menstrual bleeding associated with uterine fibroid and may fill an unmet need. The cost for elagolix-EN is $907.39 for a 28-day supply.

REFERENCES

  1. AbbVie Inc. Oriahnn prescribing information. Revised May 2020.
  2. Food and Drug Administration. FDA approves new option to treat heavy menstrual bleeding associated with fibroids in women. May 29, 2020.
  3. Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med 2020;382:328-340.
  4. Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence. Am J Obstet Gynecol 2003;188:100-107.
  5. Marsh EE, Al-Hendy A, Kappus D, et al. Burden, prevalence, and treatment of uterine fibroids: A survey of U.S. women. J Womens Health (Larchmt) 2018;27:1359-1367.
  6. Yao X, Stewart EA, Laughlin-Tommaso SK, et al. Medical therapies for heavy menstrual bleeding in women with uterine fibroids: A retrospective analysis of a large commercially insured population in the USA. BJOG 2017;124:322-330.