EMA approves Ulipristal for Preop Treatment of Uterine Fibroids

The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) grants marketing authorization for Ulipristal Acetate (Gedeon Richter) as pre-operative treatment for uterine fibroids.

Ulipristal is a selective progesterone receptor modulator used for intermittent treatment for moderate to severe symptoms of uterine fibroids in women of reproductive age. It is also used as a pre-operative treatment in women scheduled for a uterine fibroid surgery, where it helps reduce bleeding, anemia and fibroid size. It will be available as 5 mg tablet upon approval.

The application for ulipristal approval was an informed consent application, which means that reference is made to an already authorized medication upon obtaining consent to the use of their dossier in the application procedure. The reference product for Gedeon Richter Ulipristal was Esmya.

The approval further recommends that the drug should only be prescribed by physicians who are experienced in the treatment of fibroids. The common side effects of the drug include endometrial thickening, amenorrhea, and hot flushes.

However, European Union drug regulators have expressed concerns about the side effects on the liver by Esmya in the past. In December 2017, the EMA opened an investigation about liver injury by the drug, followed by a monthly recommendation of liver function test in women taking Esmya by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC).

Meanwhile, the United States FDA announced in February 2018 that it had extended the review of ulipristal new drug application (NDA) to August 2018.

  

Committee Statement

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Ulipristal Acetate effectively controls uterine bleeding in patients with symptomatic uterine leiomyomas

Nearly 50% of women with symptomatic uterine fibroid achieved amenorrhea with Ulipristal Acetate as compared to placebo, reports the results of small randomized control trial published in March issue of Journal of Obstetrics and Gynecology.

Leiomyomas are the most common indication for hysterectomy in the United States affecting nearly 70% of white women and more than 80% of black women of reproductive age. About a quarter or 50% of women experience symptoms, the most common being heavy and irregular uterine bleeding.

Many medical treatment options like nonsteroidal anti-inflammatory drugs (NSAIDs), levonorgestrel intrauterine devices, and oral and nonoral combination contraceptives are prescribed in the treatment of symptomatic fibroids but data about their efficacy is limited.

Other off-label drugs that are used for short-term management include gonadotropin-releasing hormone agonists and tranexamic acid.

This multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group phase 3, (NCT02147197) was conducted at 25 study centers across the United States.

Premenopausal women between 18-50 years of age with one or more discrete leiomyomas and uterine size 20 weeks of gestation with menorrhagia were included in the study. The researchers looked at the rate of and time to amenorrhea (no bleeding for the last 35 consecutive days of treatment) as the co-primary endpoints and Uterine Fibroid Symptoms and Quality of life (QoL) as the secondary endpoints.

Over a period of 2 years, 157 patients with similar demographics were randomized 1:1:1 to once-daily oral 5 mg ulipristal, 10 mg ulipristal, or placebo followed by a 12-week drug-free period.

Patients fared significantly better with both the doses of ulipristal, in terms of achieving amenorrhea 25 of 53 (47.2%) and 28 of 48 (58.3%) patients treated with 5 mg and 10 mg ulipristal, respectively achieved amenorrhea as compared with 1 of 56 (1.8%) of placebo-treated patients (both P <.001).

Patients on ulipristal also reported an improved quality of life and a decrease in the amount of blood loss. At the end of follow-up period decrease in volume of the leiomyomas was also observed in ulipristal treated groups as compared to placebo where an increase was noted.  

The small sample size and short duration of treatment were not enough to study the side effects but not a single patient discontinued the treatment because of side effects of the drug.

Other studies have shown that multiple 12-weeks courses of ulipristal (up to 8 coursed of 12 weeks duration each) is effective and well tolerated and maintains the efficacy and quality of life.

The authors concluded, “ulipristal may be useful for the medical management of abnormal uterine bleeding associated with uterine leiomyomas, especially for patients desiring uterine- and fertility-sparing treatment.”

Abstract

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Ulipristal acetate in medical management of fibroid

All symptomatic fibroid will eventually require treatment.

Absolute treatment is surgery consisting of  removing the myoma or the entire uterus, but there are patients  in whom Hysterectomy is not a feasible option, or patients who refuse surgery.

These patients have a choice between radiological or medical management. Radiological management consists of uterine artery embolization/ ultrasound ablation. All medical management offer short term relief and consists of progestin, aromatase inhibitors, GnRH analogues, and selective estrogen receptors modulators.  All these agents modify the hormonal milieu leading to shrinkage in size and decreasing the severity of symptoms.

Ulipristal acetate (UPA) is a possible option for medical therapy. It most common use is for preoperative shrinkage of fibroids in reproductive age group women.  It is a steroid that reversibly binds to the progesterone (P) receptor in its target tissue, acting as a potent orally active P receptor modulator. It belongs to the class of drugs known as elective P receptor modulators (SPRMs).

This study aims to investigate the long term intermittent use of UPA in relieving fibroid symptoms.  It was designed by the sponsor (PregLem S.A.) makers of ESMYA, with the involvement of academic investigators and a contract study statistician (CROS NT).

This is the first double blind RCT for UPA  by Donnez J et al published in the January issue of journal of  Fertlity  and Sterility.

Study subjects consist of premenopausal women with fibroid size between 3-12 mm in diameter, menorrhagia and uterine size less than 16 weeks. All study participants were aged between 18 and 50 years inclusive, with body mass index 18–40 (kg/m²) and regular menstrual cycles of 22–35 days with FSH ≤20 IU/L.

The subjects were assigned to receive UPA 5mg or 10 mg and matching placebos for four 12-week courses. A drug holiday was held after each course and the subsequent course was started on second menstruation during the drug free period.

The primary endpoints were percentage of subjects with amenorrhea at the end of four course treatments, the safety endpoint included number of women withdrawing from the treatment due to the adverse effects.

At the end of completion of the study, it was seen that:

• 75% of the subjects remained in the study for 20 months, demonstrating a very good compliance.
• UPA 5 and 10 mg both resulted in amenorrhea, ≥70% of subjects achieved it in a week and the average post-treatment menstrual bleeding was markedly less comparing with pretreatment bleeding.
• 73% of all subjects ended in amenorrhea with ≥25% reduction in fibroid volume at the end of treatment period.
• The endometrial changes were benign and returned to pretreatment levels in 3 months post treatment.
• Levels of E₂ remained well above postmenopausal levels, evading the fear of decreased bone mineral density.

It was concluded that treatment with four 12-week treatment courses of UPA at doses of 5 and 10 mg was well tolerated. No differences were observed between the 5 and 10 mg dosing groups. At the end of treatment cycle more than three fourth women achieved amenorrhea and a reduction in fibroid size. 

This study also showed that UPA 5 mg as an intermittent therapy can be a good medical alternative in those women with fibroid who wish to avoid surgery or surgery is contraindicated.

References:

http://www.fertstert.org/article/S0015-0282%2815%2901960-3/fulltext