During its meeting of March 2020, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended the suspension of ulipristal acetate for uterine fibroids during ongoing review of liver injury risk. Furthermore, the PRAC made new testing and treatment recommendations for fluorouracil, capecitabine, tegafur and flucytosine, and started a review of certain ifosfamide cancer medicines.
Suspension of ulipristal acetate for uterine fibroids during ongoing review of liver injury risk
The PRAC recommends women to stop taking 5-mg ulipristal acetate (Esmya and generic medicines) for uterine fibroids while a safety review is ongoing. No new patients should start treatment with the medicines, which will be temporarily suspended throughout the EU during the review.
EMA is starting its review at the request of the European Commission following a recent case of liver injury, which led to liver transplantation in a patient taking the medicine.
A 2018 EMA review concluded that there is a risk of rare but serious liver injury with ulipristal acetate medicines for the treatment of uterine fibroids, and measures were implemented to minimise the risk. However, as the new case of serious liver injury occurred in spite of adherence to these measures, EMA is starting a new review.
Cases of serious liver injury have been reported, including five that led to transplantation, out of over 900,000 patients who have been treated with ulipristal acetate for fibroids since its authorisation in 2012.
Ulipristal acetate is also authorised as a single-dose medicine for emergency contraception.
This review does not affect the single-dose ulipristal acetate emergency contraceptive (ellaOne and other trade names) and there is no concern about liver injury with these medicines.
Further information and updated recommendations will be provided once the review is concluded.
Information for patients
- Patients should stop taking ulipristal acetate for uterine fibroids (non-cancerous tumours of the womb) while EMA’s safety committee reviews data on the safety of these medicines. The review has started following a case of serious liver injury resulting in liver transplantation that has occurred in a woman taking ulipristal acetate for uterine fibroids.
- If you are taking ulipristal acetate for uterine fibroids, contact your doctor for advice on other possible treatments.
- Consult your doctor or pharmacist if you have any questions or concerns about your treatment.
- Contact your doctor immediately if you develop symptoms of liver injury such as tiredness, loss of appetite, abdominal pain, yellowing of the skin, darkening of the urine, nausea and vomiting.
- There is no concern about liver injury with the single-dose emergency contraceptive containing ulipristal acetate (ellaOne and other trade names).
Information for healthcare professionals
- Contact your patients currently being treated with ulipristal acetate for uterine fibroids as soon as possible and stop their treatment. Consider other treatment options as appropriate.
- Advise patients to immediately report signs and symptoms of liver injury (such as nausea, vomiting, right hypochondrial pain, anorexia, asthenia and jaundice).
- Liver function testing should be performed 2–4 weeks after treatment has stopped as described in the product information for the medicines.
- Do not start any new patients on ulipristal acetate for uterine fibroids.
- A direct healthcare professional communication (DHPC) will be sent on or soon after 23 March 2020 to healthcare professionals prescribing or dispensing the medicines. The DHPC will also be published on a dedicated page on the EMA website.
The following ulipristal – containing medicines are authorised and marketed in Belgium :
More information is available on the EMA website.
New testing and treatment recommendations for fluorouracil, capecitabine, tegafur and flucytosine
The PRAC recommends that patients should be tested for the lack of an enzyme called dihydropyrimidine dehydrogenase (DPD) before starting cancer treatment with medicines containing fluorouracil given by injection or infusion (drip) and the related medicines capecitabine and tegafur, which are converted to fluorouracil in the body.
As treatment for severe fungal infections with flucytosine (another medicine related to fluorouracil) should not be delayed, testing patients for DPD deficiency before they start treatment is not required.
No pre-treatment testing is needed for patients treated with topical fluorouracil (applied to the skin to treat various skin conditions).
Lack of a working DPD enzyme, which is needed to break down fluorouracil, causes fluorouracil to build up in the blood. This may lead to severe and life-threatening side effects such as neutropenia (low levels of neutrophils, a type of white blood cells needed to fight infection), neurotoxicity (damage to the body’s nervous system), severe diarrhoea and stomatitis (inflammation of the lining of the mouth).
The PRAC assessed the available data and recommended the following measures to ensure the safe use of fluorouracil and fluorouracil-related medicines:
Fluorouracil, capecitabine and tegafur
Testing of patients for DPD deficiency is recommended before starting treatment with fluorouracil injection or infusion, capecitabine and tegafur. This can be done by measuring the level of uracil (a substance broken down by DPD) in the blood, or by checking for the presence of certain mutations (changes) in the gene for DPD which are associated with an increased risk of severe side effects. Relevant clinical guidelines should be taken into consideration.
Patients with a known complete DPD deficiency must not be given fluorouracil injection or infusion, capecitabine or tegafur, as a complete lack of working DPD puts them at higher risk of severe and life-threatening side effects.
For patients with a partial DPD deficiency, a reduced starting dose of these medicines should be considered; since the effectiveness of a reduced dose has not been established, following doses may be increased if there are no serious side effects. Regular monitoring of fluorouracil blood levels in patients receiving fluorouracil by continuous infusion could improve treatment outcome.
Pre-treatment testing or dose adjustments based on DPD activity are not needed for patients using topical fluorouracil. This is because the level of fluorouracil absorbed through the skin into the body is extremely low, and the safety of topical fluorouracil is not expected to change in patients with partial or complete DPD deficiency.
Flucytosine is used to treat severe yeast and fungal infections, including some forms of meningitis (inflammation of the membranes that surround the brain and spinal cord). To avoid any delay in starting therapy, pre-treatment testing for DPD deficiency is not required.
Patients with a known complete DPD deficiency must not be given flucytosine, due to the risk of life-threatening side effects.
Patients with a partial DPD deficiency are also at increased risk of severe side effects. In case of side effects, the treating doctor should consider stopping treatment with flucytosine. Testing of DPD activity may also be considered, since the risk of severe side effects is higher in patients with a low DPD activity.
The prescribing information for doctors and patients will be updated to include the above recommendations.
The following fluorouracil, capecitabine and tegafur – containing medicines are authorised and marketed in Belgium:
- Fluorouracil : Fluorouracil Accord Healthcare (solution for injection or infusion), Fluracedyl (solution for injection), Efudix (cutaneous cream);
- Capecitabine : Capecitabine Accord, Capecitabine EG, Xeloda;
- Tegafur : Teysuno (contains tegafur in association with gimeracil and oteracil).
There is no flucytosine– containing medicine authorised and marketed in Belgium.
More information is available on the EMA website.
Review of certain ifosfamide cancer medicines
EMA has started a review of certain medicines containing ifosfamide to examine whether there is a higher risk of encephalopathy (brain disorder) with ifosfamide available as a ready-made solution or concentrate for solution than with the powder form.
Ifosfamide is used to treat different types of cancers, including various solid tumours and blood cancers such as lymphomas (cancer of white blood cells). The risk of encephalopathy is already known and reflected in the product information for these medicines.
In 2016, an investigation in France suggested an incidence of encephalopathy 3 to 4-fold higher with the ready-made solution than with the powder. Analyses carried out at the time concluded that the risk may be linked to the degradation of the active substance and impurities developing over time in the solution. As a result, the solution’s shelf-life was reduced in France. However, two recent studies, suggested that the risk of encephalopathy with the solution remains higher than the risk with the powder and a more thorough review was considered needed.
EMA will now assess the available data on the risk of encephalopathy with ifosfamide ready-made solution or concentrate for solution and recommend whether the marketing authorisations for these products should be maintained, varied, suspended or revoked.
The following ifosfamide – containing medicine is authorised and marketed in Belgium :
More information is available on the EMA website.
 Up to 8 % of the Caucasian population have low levels of a working DPD enzyme, and up to 0.5% completely lack the enzyme.
 Hillaire-Buys D, Mousset M, Allouchery M, et al. Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population. Therapies [Online]. 2019 https://doi.org/10.1016/j.therap.2019.08.001