Esmya (ulipristal acetate) and risk of serious liver injury: new restrictions to use and requirements for liver function monitoring before, during, and after treatment

More than one treatment course is authorised only in women who are not eligible for surgery, and liver function monitoring is to be carried out in all women treated with Esmya. Before initiation, discuss with women the rare risk of liver damage and advise them to seek urgent medical attention if they develop any symptoms or signs of liver injury.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 24 August 2018

• Therapeutic area: GI, hepatology and pancreatic disorders and Obstetrics, gynaecology and fertility

Post-Publication note: February 2021

Following the completion of a further EU safety review, the indication of ulipristal acetate 5mg for uterine fibroids was further restricted and the temporary suspension was lifted. This medicine should now 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. For the latest information and liver monitoring requirements, see Drug Safety Update, February 2021.

Post-publication note: March 2020

In March 2020, the licence for Esmya was suspended and a safety review initiated following a further case of liver injury requiring transplant. See Drug Safety Update for more information.

Advice for healthcare professionals:

Restricted indication and new contraindication

• Esmya is now indicated for:

  • the intermittent treatment of moderate to severe symptoms of uterine fibroids in women of reproductive age who are not eligible for surgery

  • one treatment course of pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age

• Esmya treatment is to be initiated and supervised by physicians experienced in the diagnosis and treatment of uterine fibroids

• Esmya is contraindicated in women with underlying liver disorders

Liver function monitoring

• before initiation of each treatment course: perform liver function tests; do not initiate Esmya in women with baseline alanine transaminase (ALT) or aspartate aminotransferase (AST) more than 2-times the upper limit of normal [ULN]

• during the first 2 treatment courses: perform liver function tests every month

• for further treatment courses: perform liver function tests once before each new course and when clinically indicated

• at the end of each treatment course: perform liver function tests after 2–4 weeks

• Stop Esmya treatment and closely monitor women with ALT or AST more than 3-times ULN; consider the need for specialist hepatology referral

Discuss the risk of liver damage with Esmya with women and report any suspected adverse drug reactions

• before initiation of Esmya, discuss with women the rare risk of liver damage and need for liver function testing before, during, and after each treatment course

• advise women to seek urgent medical attention if they develop any symptoms or signs of liver injury (such as tiredness, yellowing of the skin, darkening of the urine, nausea and vomiting)

• pharmacists should provide the new patient card to women when dispensing Esmya; copies of this card are included in the letter sent to healthcare professionals and are available online

• report any suspected adverse drug reactions to Esmya on a Yellow Card without delay

EU review of risk of serious liver injury

In March 2018, we announced temporary safety measures, including no new patients to be prescribed Esmya, while an EU review investigated the link between Esmya and cases of serious liver injury, including cases requiring liver transplantation.

The EU review concluded that Esmya may have contributed to the development of some of the 8 cases of serious liver injury reported for this drug. It is estimated that around 765,000 patients have been treated with Esmya worldwide to date.

The review recommended restricting the indicated population for Esmya for safety reasons and introduced measures to minimise risk of liver injury. In particular, more than one treatment course is now authorised only in women who are not eligible for surgery, and liver function monitoring is to be carried out in all women treated with Esmya.

Alert issued to healthcare professionals

On 7 August 2018, an alert was issued to UK healthcare professionals to inform them of the new measures to minimise the risk of serious liver damage. The licence holder also sent a letter by post to specialists, GPs, and pharmacists to inform them of the new advice. These restrictions replace the temporary safety measures introduced in February 2018.

Physicians should carefully consider if Esmya is an appropriate option for their patient, in view of the restricted indication,^{[footnote 1]} the new contraindication, and the liver monitoring to be undertaken as described in the letter and the updated Summary of Product Characteristics for Esmya.

In the UK, as of 13 July, we have received 1 Yellow Card report each of acute hepatitis, hepatic fibrosis, and non-alcoholic fatty liver and 8 reports of abnormal liver function tests in association with Esmya.^{[footnote 2]} Approximately 19,860 treatment courses of Esmya were dispensed in the UK between 1 April 2017 and 31 March 2018.^{[footnote 3]}

Resources available to support safe use

A Patient Card will be introduced in the medicine’s package to remind women of the need to stop treatment and contact their doctor immediately should they develop signs or symptoms of liver injury. The Card also contains a table to help women track their blood tests. Pharmacists should advise women to read the information carefully.

Copies of the card have been included in the letter to healthcare professionals sent on 1 August 2018 and are available online. For additional hard copies, contact Gedeon Richter (UK) Medical Information at 0207 604 8806 or [email protected]. This will only be required until packs with the pre-inserted Patient Card reach the market.

The physician’s guide and pathologist’s guide for Esmya have also been updated.

ellaOne

The emergency contraceptive ellaOne also contains ulipristal acetate in a single dose of 30 mg. No cases of serious liver injury have been reported with ellaOne since it was authorised in the EU in 2009 and there are no concerns or changes to its use at this time.

Report suspected adverse drug reactions on a Yellow Card

The Yellow Card Scheme is vital in helping the Medicines and Healthcare products Regulatory Agency (MHRA) to monitor the safety of all healthcare products in the UK to ensure they are acceptably safe for patients and users. Please report any suspected adverse drug reactions to Esmya without delay, via the Yellow Card Scheme.

Article citation: Drug Safety Update volume 12, issue 1; August 2018: 1.

1. Each treatment course should not exceed 3 months and should only be repeated after a break in treatment. See Summary of Product Characteristics for method of administration ↩

2. Reporters are asked to submit Yellow Card reports even if they only have a suspicion that the medicine may have caused the adverse drug reaction. The existence of an adverse drug reaction report does not necessarily mean that the medicine has caused the reaction. ↩

3. Data derived from IQVIA MIDAS 04/2017-03/2018 by MHRA, July 2018. The usage estimate is based on the assumption that each treatment course was of 3 months’ duration. The number of courses each woman takes may vary between 1 and 4 courses. The number of courses quoted is a broad estimation and is not therefore equivalent to the number of women who used Esmya. ↩

Published 24 August 2018