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The safe and rational use of ulipristal for fibroids

Dr. Siow Yew Ming Anthony
Medical Director
ASC Clinic for Women, Gleneagles Medical Centre, Singapore
20 Jun 2019
Fibroids or leiomyomas are the most common benign smooth muscle tumours of the uterus. They are often detected at screening ultrasound in asymptomatic patients. A fibroid will naturally grow until menopause and subsequently shrink when female hormone levels drop. The majority of women with fibroids are asymptomatic. When fibroids become symptomatic, they usually cause heavy menstrual bleeding leading to anaemia, iron deficiency, and tiredness. Large fibroids can also present as an abdominal mass, with pressure symptoms on the bladder or bowel, and can cause pelvic pain. Some fibroids can also impair fertility and affect pregnancy outcomes. These symptoms can negatively impact women’s quality of life (QoL) and ability to carry on daily activities. [Hum Reprod Update 2016;22:665-686]

Management of uterine fibroids
Fibroids that are <4 cm and asymptomatic can generally be monitored with annual ultrasound checks. Larger fibroids causing symptoms or fertility issues will require treatment. The treatment strategy will depend on the symptoms, character, and location of the fibroids, as well as the woman’s age and fertility desire. Common management approaches include surgery (myomectomy) and nonsurgical options like uterine artery embolization (UAE), high-intensity focus ultrasound (HIFU), and medical treatment with gonadotropin-releasing hormone (GnRH) agonists and selective progesterone receptor modulators (SPRM). [Hum Reprod Update 2016;22:665-686; Am Fam Physician 2017;95:100-107]

Although nonsurgical treatment options for fibroids avoid the risk of surgery, the concern is the risk of leaving behind a fibroid that may be cancerous. In practice, the actual risk of a fibroid being a cancer called leiomyosarcoma is exceedingly rare. Hence, for the large majority of women with fibroids, nonsurgical treatment is still considered safe. Large studies have found the risk of leiomyosarcoma to be between 1 in 2,000 and 1 in 8,300. [Gynecol Surg 2015;12:165-177]. “Similarly, local data from the KK Women’s and Children’s Hospital estimate the risk of unsuspected leiomyosarcoma at 4:4,000 or 0.1 percent,” shared Dr Siow. To help reduce the risk of missing a cancerous fibroid, special MRI scans and blood tests can be done to triage cases appropriate for surgery rather than nonsurgical treatment. [J Minim Invasive Gynecol 2018;25:507-513; Int J Gynecol Cancer 2002;12:354-361] Fibroid cancer can only be diagnosed after surgery as no preoperative biopsy testing is available.

Medical management of uterine fibroids with ulipristal
Ulipristal is the first SPRM approved for the treatment of fibroids. It is the only agent currently approved in Europe for both preoperative and intermittent treatment of symptomatic fibroids. “It is currently the only fibroid medicine that can be used for long-term (ie, >6 months), is suitable for women desiring pregnancy, and does not make surgery any more difficult compared with a GnRH agent,” Dr Siow said.

Ulipristal has been shown to reduce uterine bleeding and induce permanent fibroid size reduction. [Fertil Steril 2011;95:767-772] It can induce amenorrhoea within 7 days in more than 90 percent of patients, demonstrating its superior ability in controlling bleeding. [Fertil Steril 2014;101:1565-1573] The efficacy of ulipristal in controlling uterine bleeding has also been shown to be noninferior to that of the GnRH leuprolide. [N Engl J Med 2012;366:421-432]

Studies have shown ulipristal to be successful in shrinking fibroid size in about 70 percent of cases treated for >6 months. The fibroid size reduction is permanent with no evidence of rapid rebound growth compared with GnRH agents. Dr Siow explained that fibroid size reduction is measured by volume reduction rather than by the usual diameter measurement. Hence, a 50-percent fibroid volume reduction will translate to only about a 1-cm reduction in fibroid diameter. Nonetheless, the alleviation of fibroid symptoms, which is dependent on the fibroid volume, will be evident to the patient. [N Engl J Med 2012;366:421-432]

In patients who receive ulipristal preoperatively, data suggests that pretreatment does not negatively affect the overall myomectomy surgery. Finding the surgical planes between fibroid and womb muscles, and separating the fibroid from the womb, do not become more difficult. (Table 1) [J Minim Invasive Gynecol 2018;25:514-521]

Safe Table 01

Ulipristal has also been shown to be safe in patients wishing to conceive following fibroid treatment. A pregnancy rate of 71 percent has been reported following ulipristal treatment, with no maternal complications related to fibroids during pregnancy or after delivery. [Fertil Steril 2014;102:1404-1409] Additionally, long-term follow-up showed no significant regrowth of fibroids in this patient subgroup.

The most significant finding regarding the treatment efficacy of ulipristal comes from real-world data (PREMYA study). [Eur J Obstet Gynecol Reprod Biol 2017;208:91-96] In this study, 1,473 women awaiting fibroid surgery from 73 clinics in Europe were treated with ulipristal for 3 months and followed up for 15 months. Sixty percent of women rated their symptoms of bleeding, pain, and QoL ‘much improved’ or ‘very much improved’ after ulipristal treatment. Only 38 percent of women needed subsequent surgery to resolve their symptoms, suggesting that 3 months of ulipristal can reduce the need for surgery in up to 60 percent of cases, thus bringing tremendous hope for women with fibroids.

Monitoring patients on ulipristal
In late 2017, sporadic cases of liver failure were reported in women using ulipristal for fibroids. A thorough investigation revealed up to eight cases of associated liver injury out of more than 765,000 women treated with ulipristal. This constitutes a drug-induced liver injury (DILI) risk of 8:765,000 or 0.001 percent. Dr Siow stressed that this DILI risk is in fact lower than that of commonly prescribed medicines like statins (Zocor), fluconazole (Diflucan), and amoxicillin/clavulanic acid (Augmentin). Additionally, an in-depth review of women with liver injury showed that a majority of them had pre-existing liver conditions such as viral hepatitis, cirrhosis, and autoimmune hepatitis.

Nonetheless, the European Medicines Agency Pharmacovigilance Risk Assessment Committee has recommended that women receiving ulipristal should have liver function tests done before, during, and after each treatment course for the first 6 months. [https://www.ema.europa.eu/en/medicines/human/referrals/esmya, accessed 24 April 2019]

The Royal College of Obstetricians & Gynaecologists has also published treatment guidelines for ulipristal and fibroids, recommending ulipristal for women who are ineligible for surgery, ie, those who wish to preserve fertility, are perimenopausal, or decline surgery. [https://www.rcog.org.uk/en/guidelines-research-services/guidelines/esmya-ulipristal-acetate---mhra-safety-alert, accessed 24 April 2019]

Conclusion
There are many treatment options for fibroids today. Dr Siow emphasized the active role of the patient in choosing her treatment, and the physician’s duty in presenting the risk-benefit information of each treatment to help patients make their decision. To put things in perspective, there is a potential 0.01–0.1-percent risk of cancer existing in some fibroids, surgical treatment entails <0.1–0.5-percent risk of complications including death, and current data reveals a 0.001-percent risk of liver injury with ulipristal. “Our job is to provide patients with factual and balanced information, so they can make an informed decision on which treatment to proceed with safely,” Dr Siow added.

Dr Siow strongly feels that ulipristal offers a real potential for fibroid management – relieving heavy bleeding, anaemia, and pain with associated QoL improvement, potential shrinkage of fibroid volume to allow for easier laparoscopic keyhole surgery and, in some cases, complete avoidance of surgery.
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Most Read Articles
09 Jul 2019
Patients who had undergone aortic valve replacement (AVR) have shorter life expectancy than the general population, a study has found. Apart from being substantial, this loss in life expectancy increases with younger age.
5 days ago
The consumption of red and processed meats does not seem to affect the likelihood of symptom relapse among Crohn’s disease (CD) patients in relapse, reports a recent study.
Pearl Toh, 08 Jul 2019
High intake of red meat during midlife was associated with a greater risk of cognitive impairment later in life among Chinese adults, according to data from approximately 20 years of follow-up of the Singapore Chinese Health Study (SCHS) cohort.
Stephen Padilla, 09 Jul 2019
A recent study reports a highly uniform practice of electroconvulsive therapy (ECT) in Singapore, with rates and indications consistent with those applied by other developed nations. Moreover, ECT is more commonly used for schizophrenia in the country.