Interview on Ulipristal Acetate for Treatment of Uterine Leiomyomas

Educational Objectives

The goal of this program is to improve diagnosis and treatment of uterine fibroids. After hearing and assimilating this program, the clinician will be better able to:

1. Compare and contrast the safety and efficacy of ulipristal and leuprolide for treatment of uterine fibroids.

2. Explain the mechanism of action of ulipristal.

Summary

Overview: prevalence of uterine fibroids 70% in whites and 80% in blacks; however, only 25% to 50% of population presents to gynecologic clinician; complaints may include heavy bleeding, dysmenorrhea, and pressure symptoms affecting bladder or bowel

Evaluation: clinician should ascertain whether patient has ongoing interest in fertility; patients who have completed childbearing may benefit from hysterectomy; those who want to preserve uterus may undergo myomectomy, but resulting weakness of uterine wall often necessitates cesarean delivery

Medical management: heavy bleeding or painful menses may be treated by targeting uterine lining; options include oral contraceptives (which thin lining); if fibroids not distorting cavity of uterus, clinician may insert intrauterine device that releases progestin; depot leuprolide (Lupron Depot) commonly used in patients who do not respond to other hormonal treatments; leuprolide reduces stimulation of uterine lining and fibroids by estrogen and often reduces size of fibroids and thins lining of uterus; however, drug induces pseudomenopausal state characterized by hot flashes, joint stiffness, and vaginal dryness

Ulipristal: reduces size of fibroids and bleeding and associated with fewer side effects; ulipristal selective progesterone receptor modulator and steroid-like molecule; it competes with progesterone at receptor but does not induce downstream effects of progesterone (fibroids grow in response to both estrogen and progesterone); ulipristal partially blocks progesterone receptor in uterus, causing fibroids to stop growing or shrink; ulipristal also targets lining of uterus, arresting bleeding; progestin-like action of drug on hypothalamic-pituitary axis leads to less frequent ovulation (but agent not used as contraceptive)

Design of clinical trial by speaker’s group: double-blinded trial employed placebo control; design included 2 12-wk courses of treatment; every patient received ulipristal for at least one course; primary end points rate of amenorrhea and time to amenorrhea

Outcomes: as in European trials, time to amenorrhea (time from start of taking drug to cessation of bleeding) 7 to 10 days; 45% to 50% of patients had persistent amenorrhea after taking drug for 35 days; study population included more black than white women; side effects fewer than in patients treated with gonadotropin releasing-hormone (GnRH) agonists; 5% to 10% of patients on active treatment reported mild hot flashes, but no patients stopped drug for this reason; small percentage of patients in both active treatment and placebo groups reported mild headache

Dose: 5-mg dose used in Europe; speaker’s study not powered to compare 5- and 10-mg doses; rate of amenorrhea slightly different between groups, but time to amenorrhea similar

Experience with ulipristal: >765,000 women in Europe have used ulipristal; recent reports describe liver problems in 8 women; European authorities recommend liver function studies at baseline and 1 and 2 mo, and limitation to single cycle of ulipristal in patients planning to undergo surgery; Food and drug administration (FDA) working with manufacturer to monitor issue but has not approved ulipristal in United States; liver toxicity not observed in speaker’s study

Comparison with other trials: PEARL trials conducted in Europe reported rates of amenorrhea ≈80%; 80% to 90% of women in these trials white, and mean body mass index (BMI) lower than that in US trial; in contrast, mean BMI 30 in patients in US trial, and >50% of women black, so population more symptomatic than women enrolled in European studies

Indications: if approved in United States, ulipristal could compete with GnRH agonists, but not appropriate as first-line therapy; ulipristal may have efficacy similar to that of GnRH agonist with fewer side effects; ulipristal used preferentially (over GnRH agonists) in Canada

Preoperative use: experience from PEARL trials showed that in patients on ulipristal, shrinkage of fibroids and time to effect similar to that achievable with GnRH agonists; fibroids regrow to pretreatment size if drug discontinued; as preoperative agent, ulipristal may reduce anemia, intraoperative bleeding, and need for transfusion, especially in patients undergoing myomectomy

Similar compounds: vilaprisan selective progesterone receptor modulator similar to ulipristal and being studied in clinical trials; also being considered as treatment for endometriosis

Concerns: long-term management of patients on ulipristal needs to be studied; mechanism that produces rare liver problems unknown

Future for ulipristal: ulipristal available in United States (in 30-mg dose) for postcoital contraception; clinicians should await decision from FDA before using drug for other indications; clinical trials now evaluating ulipristal for endometriosis

Link to full article: https://journals.lww.com/greenjournal/Abstract/2018/11000/Ulipristal_Acetate_for_Treatment_of_Uterine.22.aspx

Readings

Baggio S et al: Influence of ulipristal acetate therapy on uterine fibroid-related symptoms and on uterine and fibroid volumes and vascularity indices assessed by ultrasound. J Ultrasound Med 2018 Sep;37(9):2215-2223; Donnez J: Liver injury and ulipristal acetate: an overstated tragedy? Fertil Steril 2018 Sep;110(4):593-595; Donnez J et al: Ulipristal acetate for the management of large uterine fibroids associated with heavy bleeding: a review. Reprod Biomed Online 2018 Aug;37(2):216-223; Donnez J et al: Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421-32; Donnez J et al: Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409-20; Liu JH et al: Ulipristal acetate for treatment of uterine leiomyomas: a randomized controlled trial. Obstet Gynecol 2018 Oct 5 [Epub ahead of print]; Nogales FF et al: Endometrial changes in surgical specimens of perimenopausal patients treated with ulipristal acetate for uterine leiomyomas. Int J Gynecol Pathol 2018 Nov;37(6):575-580.

Disclosures

For this program, the following has been disclosed: Dr. Liu is a consultant to Allergan and Pfizer. He has been involved in clinical trials funded by Allergan, AbbVie, Bayer, Ferring Pharmaceuticals, and Palatin Technologies. Dr. Schorge reported nothing to disclose. The planning committee reported nothing to disclose. In his lecture Dr. Liu presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Liu was recorded as a special collaboration between Audio Digest and Obstetrics & Gynecology, the official journal of the American College of Obstetricians and Gynecologists. Dr Liu’s paper, “Ulipristal acetate for treatment of uterine leiomyomas: a randomized controlled trial,” was published in Obstetrics & Gynecology, Vol. 132, Issue 5, November 2018. For more information on the American College of Obstetricians and Gynecologists and Obstetrics & Gynecology, please visit acog.org. For more information on CME offerings from the University of California, San Francisco, please visit meded.ucsf.edu. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OB660101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.