Ulipristal acetate 5mg (Esmya): further restrictions due to risk of serious liver injury
The indication of ulipristal acetate 5mg for uterine fibroids has been further restricted due to the risk of serious liver injury and liver failure, with some cases requiring liver transplantation. Although the temporary suspension has been lifted, this medicine should only be used for intermittent treatment of moderate to severe symptoms of uterine fibroids before menopause and when surgical procedures (including uterine fibroid embolisation) are not suitable or have failed.
Advice for healthcare professionals:
- ulipristal acetate 5mg for uterine fibroids has been associated with cases of serious liver injury and liver failure (requiring transplantation in some cases); the licence was temporarily suspended in March 2020 to allow a further review of these risks
- although the temporary suspension has been lifted, the indication for ulipristal acetate 5mg has been further restricted – it should be used only for intermittent therapy of moderate to severe uterine fibroid symptoms before menopause and when surgical procedures (including uterine fibroid embolisation) are not suitable or failed
- ulipristal acetate 5mg should no longer be prescribed for controlling symptoms of uterine fibroids while waiting for surgical treatment
- if ulipristal acetate 5mg is felt to be an appropriate therapy, talk about the risks and benefits with patients before prescribing so they can make an informed decision about treatment options; this conversation should include discussion of:
- all available treatment options for moderate to severe symptoms of uterine fibroids, and the advantages and risks of these depending on personal situation
- the potential risk of liver injury and liver failure with ulipristal acetate 5mg, which in rare cases has led to liver transplantation
- signs and symptoms of liver injury and what to do if they occur
- do not use ulipristal acetate 5mg in patients with an underlying liver disorder
- continue to follow advice to monitor liver function according to the recommended schedule of liver function tests before, during, and after treatment courses (see reminder below)
- report suspected adverse drug reactions associated with ulipristal acetate 5mg on a Yellow Card
Advice to give to patients:
- infrequent but serious cases of liver damage (with some cases requiring a liver transplant) have been reported in association with ulipristal acetate 5mg for uterine fibroids
- ulipristal acetate 5mg can only be used for intermittent treatment of moderate to severe symptoms of uterine fibroids if:
- you have not experienced menopause; and
- an operation or embolisation procedure for uterine fibroids is not suitable for you or these procedures have not worked
- blood tests are needed before treatment is started, during treatment, and 2–4 weeks after treatment to check your liver is functioning normally
- stop taking your ulipristal acetate tablets and speak with your doctor immediately if you get any signs of liver damage such as yellowing of the skin or eyes, dark urine, or nausea or vomiting
- carefully read the patient card included in the package and the leaflet that accompanies your medicines and keep it safe in case you need to read it again
Risk of serious liver injury
Background to the risks and measures previously taken
Ulipristal acetate 5mg (Esmya and generics) was first authorised in 2012 for intermittent or pre-operative treatment of moderate to severe symptoms of uterine fibroids in women of reproductive age.
In 2018, a European safety review was conducted due to 4 cases reported worldwide of severe liver injury resulting in liver transplantation. Several measures were introduced in 2018 to minimise the risk of severe liver injury. See Drug Safety Update, August 2018.
Latest review and new advice
In 2020, a fifth case of severe liver injury resulting in liver transplantation was reported, prompting a further European review. While this further review was conducted, the licences for all ulipristal acetate 5mg medicines were temporarily suspended (Drug Safety Update, March 2020). Esmya 5mg tablets were recalled from patients, pharmacies and wholesalers in the UK on 18 March 2020.
The temporary suspension has now been lifted, but the indication for ulipristal acetate 5mg has been further restricted. The review recommended that the risk of severe liver injury does not justify its use for the pre-operative treatment of uterine fibroids. However, the review considered that the benefits of ulipristal acetate 5mg in controlling fibroids may outweigh this risk in women who have no other treatment options (see public assessment report from the European Medicines Agency).
As such, Esmya can be used for intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women who have not reached menopause and when surgical procedures (including uterine fibroid embolisation) are not suitable or have failed
The Commission on Human Medicines’ Medicines in Women’s Health Expert Advisory Group (MWHEAG) has considered the safety data and advised that physicians should carefully consider if ulipristal acetate 5mg is an appropriate option for their patient, and accurately and thoroughly discuss the benefits and risks of ulipristal acetate 5mg with them before prescribing. This conversation should include the risk of liver injury and liver failure, including rare cases requiring liver transplantation associated with ulipristal acetate 5mg.
NICE guidance NG88 Heavy Menstrual Bleeding should be considered for clinical guidance on appropriate therapies for symptoms of uterine fibroids. All available treatment options for symptoms of uterine fibroids should be discussed with patients, including the advantages and risks of these depending on their personal situation. Surgical procedures and uterine fibroid embolisation (if available) should be considered, taking into account the patient’s preferences and plans for fertility.
The product information for medicines containing ulipristal acetate 5mg has been amended and a letter sent to healthcare professionals to inform them of the latest safety advice. The prescribing guide for physicians and the patient card will also be updated.
The frequency of occurrence of liver failure with ulipristal acetate 5mg is unknown and no patient risk factors could be identified from the available data. Since authorisation and to date, we have received 20 suspected adverse drug reaction reports of liver disorders with the use of Esmya in the UK. None report liver transplant or death. In the UK, Esmya has been suspended since March 2020.
Reminder of liver function monitoring
Ulipristal acetate 5mg is contraindicated in patients with an underlying hepatic disorder.
Liver function tests must be performed before starting treatment with ulipristal acetate 5mg. Treatment must not be initiated if transaminases (alanine transaminase (ALT) or aspartate aminotransferase (AST)) exceed 2-times the upper limit of normal (ULN).
During treatment, liver function tests must be performed monthly during the first 2 treatment courses. For further treatment courses, liver function must be tested once before each new treatment course and when clinically indicated.
If a patient shows signs or symptoms compatible with liver injury (fatigue, asthenia, nausea, vomiting, right hypochondrial pain, anorexia, jaundice), treatment should be stopped, and the patient investigated immediately. Liver function tests should be performed urgently.
Stop treatment if transaminase levels (ALT or AST) are greater than 3-times the ULN and closely monitor patients. The need for specialist hepatology referral should be considered.
Liver function tests should also be performed 2–4 weeks after treatment has stopped.
ellaOne (ulipristal acetate 30mg)
The emergency contraceptive ellaOne also contains ulipristal acetate in a single dose of 30mg. No concern has been raised about serious liver injury with ellaOne and there are no changes to its use.
Report suspected reactions on a Yellow Card
Please continue to report suspected adverse drug reactions to the Yellow Card scheme.
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
- the Yellow Card website
- the Yellow Card app; download from the Apple App Store or Google Play Store
- some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.
Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.
Article citation: Drug Safety Update volume 14, issue 7: February 2021: 1.