Risk of serious liver injury with Esmya (ulipristal acetate)

HSA would like to bring to the attention of healthcare professionals the risk of serious liver injury associated with the use of Esmya^® (ulipristal acetate 5mg). Overseas cases of serious liver injury have been reported in women who had received treatment with Esmya^®, including four cases which required liver transplantation. At this time, this safety concern has not been observed with another registered product containing the same active ingredient (Ella^®, ulipristal acetate 30mg) used for emergency contraception.

Background

Esmya^® (Zuellig Pharma Pte Ltd) is an oral selective progesterone receptor modulator (SPRM) that has been registered in Singapore since November 2014. It is indicated for pre-operative treatment, as well as intermittent treatment, of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. The treatment consists of 5mg once daily for treatment courses of up to three months each. Esmya^® exerts a direct action on fibroids, reducing their size through inhibition of cell proliferation and induction of apoptosis. Esmya^® also has a direct effect on the endometrium, which contributes to the reduction in uterine bleeding.

Overseas post-marketing cases of liver injury with Esmya¹

Esmya^® was first authorised in the European Union in February 2012. As of February 2018, the post-marketing exposure to Esmya^® was estimated at approximately 200,000 to 275,000 patient-years, assuming a mean treatment duration of three months. From February 2012 to February 2018, 105 post-marketing cases of hepatic disorders have been reported overseas with the use of Esmya^®, of which 34 cases were assessed to be serious. Esmya^® was considered as a potential contributing factor for causing liver injury in eight of the serious cases, including four cases of acute liver failure leading to liver transplantation. A contributing role of Esmya® in the development of acute liver failure in two of the cases was assessed to be probable, while insufficient information was available to either conclude or rule out a causal relationship with Esmya® for the remaining two cases.

For the other four serious cases of liver injury, although a causal role of Esmya^® was considered possible, available information was insufficient to draw firm conclusions on causality. The possible causal associations for these cases were mainly supported by positive de-challenge, absence of other confounding factors, or explanations for the observed liver injury.

At this time, the mechanism by which Esmya^® could potentially cause liver injury remains uncertain, and no clear pattern in the timing between Esmya^® treatment and the occurrence of liver injury has been identified. Based on the reported post-marketing cases of potential liver injury with Esmya^®, regardless of causality, the peak time-to-onset of liver injury is approximately 140 days, with the majority of the reported potential drug-induced liver injuries occurring within one and eight months of starting treatment with Esmya^® (i.e. two treatment cycles, including two months of treatment-free interval).

International regulatory actions^2-4

The European Medicines Agency (EMA), New Zealand Medsafe and Health Canada have conducted safety reviews on this risk, following reports of serious liver injury leading to liver transplantation after treatment with Esmya^®. Their reviews took into consideration the available data from non-clinical and clinical studies, spontaneously reported post-marketing data, as well as information from scientific literature. Based on the review of available information, all three agencies had concluded that the use of Esmya^® (or Fibristal, the brand marketed in Canada) could have contributed to the development of serious liver injuries, and additional measures should be implemented to mitigate this risk. These included contraindicating the use of Esmya^® in women with underlying liver disorders, requiring liver function monitoring to be performed before, during and after stopping treatment with Esmya^®, as well as restricting the use of multiple treatment courses of Esmya^® to women who were not eligible for surgery for treatment of the fibroids.

Local situation and HSA’s advisory

As of June 2019, HSA has received two non-serious local adverse event reports of elevations in liver function tests that were assessed to be possibly related to treatment with Esmya^®. In both cases, the increase in liver enzymes were less than three times the upper limit of normal, and were observed approximately two weeks or three months after the initiation of treatment with Esmya®. Treatment discontinuation was reported in one case, with a subsequent decrease in the patient’s liver enzymes approximately one month later.

HSA has reviewed the available information on liver injury associated with Esmya^® and assessments conducted by other regulatory agencies. We took into consideration our local adverse event reports, expert opinions from local clinicians and the company-initiated amendments to the local Esmya^® package insert (PI). To mitigate the risk of serious liver injury associated with the use of Esmya^®, the company will be strengthening the local PI of Esmya^® to contraindicate its use in patients with underlying liver disorders, as well as recommend more stringent criteria for liver function monitoring (i.e. before starting each treatment course, monthly during the first two treatment courses, and two to four weeks after stopping treatment with Esmya^®). The indications for Esmya® will also be revised to clarify its use as a single treatment course when used in the pre-operative setting, and to restrict its use to adult women of reproductive age not eligible for surgery when used for the intermittent treatment of moderate to severe symptoms of uterine fibroids. In addition, Zuellig Pharma has developed a patient information brochure, for distribution to patients through their healthcare professionals, to inform patients about the potential risk and the signs and symptoms of liver injury to look out for during treatment with Esmya^®. This brochure has been reviewed and approved by HSA.

Healthcare professionals are advised to take into consideration the above safety information when prescribing Esmya^®. They may wish to consider using the patient information brochure to counsel patients treated with Esmya^® on the need to monitor for signs and symptoms of liver injury (e.g. yellowing of the skin, fatigue or excessive tiredness, nausea and vomiting) during and after treatment. Healthcare professionals are also encouraged to report to HSA any suspected cases of liver injury related to the use of Esmya^®.

References

Healthcare professional, Industry member, Therapeutic Products

Published: 13 Sep 2019

Safety Alerts

12 Dec 2019