Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 9-12 March 2020

PRAC starts review of certain ifosfamide cancer medicines

At its monthly meeting, EMA’s safety committee (PRAC) has started a review of 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 medicine is given into a vein and is available as a ready-made solution and a concentrate for solution in France and Germany, as well as a powder for solution for infusion. In most other EU Member States, it is only available as powder.

Following studies suggesting that the risk of encephalopathy with the solution is higher than the risk with the powder, the PRAC will assess the available data on this risk and recommend whether the marketing authorisations for these products should be maintained, varied, suspended or revoked.

More information is available below.

PRAC provides new testing and treatment recommendations for fluorouracil, capecitabine, tegafur and flucytosine

The PRAC has recommended that patients receiving fluorouracil given by injection or infusion (drip) and the related medicines capecitabine and tegafur, which are converted to fluorouracil in the body, should be tested for the lack of an enzyme called dihydropyrimidine dehydrogenase (DPD) before starting treatment.

For flucytosine, another medicine that gets converted to fluorouracil in the body, pre-treatment testing is not required, in order not to delay start of treatment of patients with severe yeast and fungal infections, including some forms of meningitis.

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 (DPD deficiency), which is needed to break down fluorouracil, causes fluorouracil to build up in the blood, which 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).

More information is available below.

PRAC recommends suspension of ulipristal acetate for uterine fibroids during ongoing review of liver injury risk

The PRAC has recommended, as a precautionary measure, that women should stop taking 5-mg ulipristal acetate (Esmya and generic medicines) for uterine fibroids while a safety review started this month is ongoing. No new patients should start treatment with these medicines.

The start of the review follows a recent case of liver injury, which led to liver transplantation in a patient taking the medicine. 

A 2018 PRAC review concluded that there is a risk of rare but serious liver injury with ulipristal acetate medicines for uterine fibroids, and measures were implemented to minimise the risk. However, as the new case of serious liver injury occurred despite adherence to these measures, the Committee has started 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 out liver injury with these medicines.

More information is available below.

Article-31 referral: Fluorouracil and fluorouracil related substances (capecitabine, tegafur and flucytosine) containing medicinal products

Article-31 referral: Ifosfamide solutions

Article-31 referral: Ulipristal acetate 5mg medicinal products 

Glossary:

• Safety signal assessments. A safety signal is information on a new or known adverse event that is potentially caused by a medicine and that warrants further investigation. Signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature. More information can be found under Signal management.
• Periodic safety update reports, abbreviated as PSURs, are reports prepared by the marketing authorisation holder to describe the worldwide safety experience with a medicine in a defined period after its authorisation. PSURs for medicinal products that contain the same active substance or the same combination of active substances, but have different marketing authorisations and are authorised in different EU Member States, are jointly assessed in a single assessment procedure. More information can be found under .
• Risk management plans, abbreviated as RMPs, are detailed descriptions of the activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicines. Companies are required to submit an RMP to EMA when applying for a marketing authorisation. RMPs are continually updated throughout the lifetime of the medicine as new information becomes available. More information is available under Risk management plans.
• Post-authorisation safety studies, abbreviated as PASSs, are studies carried out after a medicine has been authorised to obtain further information on its safety, or to measure the effectiveness of risk-management measures. The PRAC assesses the protocols (aspects related to the organisation of a study) and the results of PASSs. More information can be found under Post-authorisation safety studies (PASS).
• Referrals are procedures used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines. In a referral related to safety of medicines, the PRAC is requested by a Member State or the European Commission to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the EU. More information can be found under Referral procedures: human medicines.