Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer’s approved product information, a drug information centre or some other appropriate source.

Approved indication: fibroids
Esmya (Vifor Pharma)
5 mg tablets
Australian Medicines Handbook section 17.1.3

Ulipristal acetate is a progesterone receptor modulator that has previously been approved as a postcoital contraceptive.1 As progesterone promotes the growth of uterine fibroids, blocking its receptor may reduce their size. The dose used for this indication can inhibit ovulation and lead to amenorrhoea which will be of benefit to women who have heavy menstrual bleeding related to their fibroids.

Treatment should begin in the first week of a menstrual period. The single daily dose is rapidly absorbed. There is extensive metabolism involving cytochrome P450 3A4. Ulipristal should therefore not be taken with inducers of this enzyme, such as carbamazepine, phenytoin and St John’s wort, or with inhibitors such as erythromycin. The half-life of ulipristal is about 38 hours with most of the metabolites being excreted in the faeces. No studies have been done in women with impaired hepatic or renal function.

The approval of ulipristal for the treatment of fibroids appears to have been mainly based on four trials (see Table).2-5 PEARL I and II were short term while PEARL III and IV studied repeated courses of treatment.

Table - Efficacy of ulipristal in women with fibroids

Trial

Total number of patients

 Duration of
 treatment

Proportion of patients with amenorrhoea
after treatment

 

 

 

Ulipristal
5 mg

Ulipristal
10 mg

Placebo

Leuprorelin

PEARL I2

242

 13 weeks

73%

82%

6%

PEARL II3

307

 13 weeks

75%

89%

80%

PEARL III4

209

 Four 12–week  courses  (107  women)

90%

PEARL IV5

451

 Four 12–week  courses (291 

 women)

63%

73%

Single three-month course

PEARL I enrolled women with anaemia as a result of heavy periods related to fibroids. These women were planning to have surgical treatment. There was a placebo group of 48 women, while 96 were randomised to take ulipristal 5 mg and 98 to take ulipristal 10 mg. After 13 weeks, bleeding was significantly reduced in more than 90% of the women taking ulipristal compared with 19% of the placebo group. Amenorrhoea was reported by 73% of the women taking ulipristal 5 mg and by 82% of those taking 10 mg. Only 6% of the placebo group had amenorrhoea. MRI showed that the median total fibroid volume had decreased by 21% with ulipristal 5 mg and by 12% with 10 mg while there had been a 3% increase in the volume measured in the placebo group.2

PEARL II enrolled 307 women with heavy bleeding who were eligible for surgical treatment of their fibroids. In this trial daily ulipristal was compared to monthly injections of leuprorelin, an agonist of gonadotrophin-releasing hormone. After 13 weeks, bleeding had been controlled in 90% of the women who took ulipristal 5 mg and 98% of those taking 10 mg. It was also controlled in 89% of the women given leuprorelin. These differences showed ulipristal was not inferior to leuprorelin, but leuprorelin had a greater effect on fibroid size. The total volume of the three largest fibroids in each patient was reduced by a median of 36% with ulipristal 5 mg, 42% with ulipristal 10 mg and by 53% with leuprorelin.3

Repeated courses

In PEARL III 209 women with heavy bleeding and at least one fibroid took open-label ulipristal 10 mg for three months. This was followed by double-blind treatment with norethisterone or a placebo for 10 days. The women could then opt to repeat this regimen up to three times giving a total of up to four courses. The primary outcome of the study was amenorrhoea. This was achieved by 79% of the women after the first course of ulipristal. Among the 107 women who had four courses of treatment, 90% had amenorrhoea. The three largest fibroids, seen on ultrasound scans, shrunk by a median of 45% after one course and 72% after four courses. In the women who took norethisterone, menstruation resumed more rapidly and blood loss was less than in the placebo group.4

PEARL IV had a similar study population and also had amenorrhoea as a primary end point. The 451 women were randomised to take ulipristal 5 mg or 10 mg in 12-week courses. The interval between each course depended on the timing of menstruation. At the end of each of the first two treatment courses 62% of the women taking 5 mg and 73% of those taking 10 mg had amenorrhoea.6 For patients who completed the protocol of four treatment courses the corresponding figures were 63% and 73%. After four treatment courses the three largest fibroids seen on ultrasound had reduced in volume by around 72% in both groups.5

Safety

The common adverse effects of ulipristal include headache, nausea and abdominal pain. The actions of ulipristal may cause some women to experience hot flushes. In the comparison with leuprorelin approximately 25% of the women taking ulipristal had at least one hot flush compared with 65% of those taking leuprorelin.3 Ulipristal causes changes in the endometrium. This is one reason for having intermittent courses of therapy. An annual ultrasound is recommended. If there is persistent thickening of the endometrium, a biopsy may be indicated to exclude malignancy. Some women will develop ovarian cysts.

Although ulipristal at the recommended dose will suppress ovulation in most women, others will still be at risk of pregnancy. A non-hormonal contraceptive is recommended during treatment. If pregnancy occurs there is little information about the effects of ulipristal on the fetus. It is contraindicated in pregnancy and lactation.

The effect of repeated courses on fertility is uncertain. For most women menstruation resumes within a month of stopping ulipristal.4,6

Conclusion

The role of ulipristal will be determined by each patient’s problems. While surgery will remove fibroids, this may not be appropriate for women planning a future pregnancy. It is possible that ulipristal could reduce the size of the fibroids to enable less invasive surgery. For women who do not want surgery more research will be needed on repeated courses of ulipristal.

Although a 10 mg dose was studied in the trials (see Table), 5 mg is the approved dose in Australia.

Read about The Transparency Score  manufacturer provided additional useful information


The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the website of the European Medicines Agency and the Therapeutic Goods Administration.