Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8-11 March 2021

News 12/03/2021

Review of thalassaemia medicine Zynteglo started

EMA’s human safety committee (PRAC) has begun a safety review of the medicine Zynteglo, a gene therapy authorised to treat the rare blood condition beta thalassaemia.

The review follows a case of acute myeloid leukaemia, a cancer of the blood, in a patient treated with a related investigational medicine, bb1111. This medicine uses the same modified virus (known as a viral vector) as Zynteglo, to deliver a gene into body cells.

So far, no cases of leukaemia have been reported with Zynteglo itself. The company responsible for developing both medicines has paused supply of Zynteglo while the evidence is examined.

PRAC will now examine the evidence thoroughly at EU level, working closely with experts from EMA’s Committee for Advanced Therapies (CAT), which is responsible for assessing this type of medicine, and decide on any relevant regulatory action for Zynteglo.

More information is available below.

Benefits of ifosfamide solutions continue to outweigh risks

PRAC concluded that the benefits of ifosfamide solutions for infusion continue to outweigh their risks in the treatment of different types of cancers, including various solid tumours and blood cancers such as lymphomas (cancer of white blood cells).

The review was started because two recent studies1,2 suggested that the risk of encephalopathy (brain disorders) with ifosfamide supplied in solution forms is higher than with the powder form.

PRAC considered all available data and concluded that an increased risk of encephalopathy with ifosfamide supplied as a solution could neither be confirmed nor excluded due to limitations in the data. PRAC recommended that the existing warning on ifosfamide-induced encephalopathy in the product information should be updated with the latest information on this side effect. For more information, see EMA’s public health communication.

PRAC investigating cases of thromboembolic events after vaccination with COVID-19 Vaccine AstraZeneca - vaccine’s benefits currently still outweigh risks

The PRAC is reviewing all cases of thromboembolic events, and other conditions related to blood clots, reported post-vaccination with Vaxzevria (previously COVID-19 Vaccine AstraZeneca).

There is currently no indication that vaccination has caused these conditions, which are not listed as side effects with this vaccine. The position of the PRAC is that the vaccine’s benefits continue to outweigh its risks and the vaccine can continue to be administered while investigation of cases of thromboembolic events is ongoing.

EMA will further communicate as the assessment progresses. For more information see EMA’s update.

PRAC concludes safety signal of anaphylaxis with COVID-19 Vaccine AstraZeneca

Following the assessment of a safety signal regarding cases of anaphylaxis (severe allergic reactions) with Vaxzevria (previously COVID-19 Vaccine AstraZeneca), PRAC has recommended an update to the product information to include anaphylaxis and hypersensitivity (allergic reactions) as side effects in section 4.8, with an unknown frequency, and to update the existing warning to reflect that cases of anaphylaxis have been reported.

The update is based on a review of 41 reports of possible anaphylaxis seen among around 5 million vaccinations in the United Kingdom3. After careful review of the data, PRAC considered that a link to the vaccine was likely in at least some of these cases.

Anaphylaxis is a known side effect that may occur, very rarely, with vaccines, and is already included in the risk management plan for Vaxzevria (previously COVID-19 Vaccine AstraZeneca) as a potential risk. Therefore, the product information already contains a warning about anaphylactic reactions. This information also highlights the need for appropriate medical treatment to be readily available in case of an anaphylactic event with the vaccine, and a recommendation that people receiving the vaccine be monitored for at least 15 minutes after vaccination is already included. Any person developing such a reaction after the first dose of the vaccine should not be given a second dose. This advice, which is aligned across all the COVID-19 vaccines authorised in the EU, remains unchanged and the update to the product information does not require any change in clinical practice.

PRAC reviews signal of low levels of blood platelets with COVID-19 vaccines

PRAC has started a review of a safety signal to assess reports of immune thrombocytopenia in patients who received any of the three COVID-19 vaccines:ComirnatyVaxzevria (previously COVID-19 Vaccine AstraZeneca) and Spikevax (previously COVID-19 Vaccine Moderna).

Several cases of immune thrombocytopenia (a disorder characterised by low levels of blood platelets that can lead to bruising and bleeding) were reported in the EudraVigilance database.

In the EU, enhanced safety monitoring is in place for COVID-19 vaccines to pick up reports of adverse effects, so called adverse events of special interest (AESI). Immune thrombocytopenia has been identified as an AESI after vaccination and is closely monitored by EMA, the national competent authorities and the marketing authorisation holder. After reviewing the safety reports received so far, the PRAC decided to request an in-depth review of all available data, including case reports, clinical trials and the published literature, from the respective marketing authorisation holders for these vaccines.

At this stage, it is not yet clear whether there is a causal association between vaccination and the reports of immune thrombocytopenia. These reports point to a ‘safety signal’ - information on new or changed adverse events that may potentially be associated with a medicine and that warrants further investigation.

PRAC will evaluate all the available data to decide if a causal relationship is confirmed or not. In cases where a causal relationship is confirmed or considered likely, regulatory action may be necessary and this usually takes the form of an update of the summary of product characteristics and the package leaflet.

EMA will further communicate on the outcome of the PRAC’s review.

PRAC reviews signal of localised swelling related to dermal fillers with Comirnaty

PRAC has started a review of a safety signal to assess reports of localised swelling after vaccination with COVID-19 vaccine Comirnaty in people with a history of injections with dermal fillers (soft, gel-like substances injected under the skin). Skin reactions such as site itching, facial swelling and pruritus where fillers had been previously injected were initially reported by the Norwegian Medicines Agency in one patient.

A review of reports in EudraVigilance highlighted a limited number of cases of localised swelling in people with dermal fillers potentially associated with the administration of Comirnaty. After considering the available evidence, PRAC has requested from the marketing authorisation holder a review of all cases including reports, clinical trials and the published literature.

PRAC will keep investigating this signal and will consider any regulatory action, including updating the product information of Comirnaty.

New safety information for healthcare professionals

As part of its advice on safety-related aspects to other EMA committees, the PRAC discussed direct healthcare professional communications (DHPCs) containing important safety information for Xeljanz and Eylea.

Xeljanz: initial clinical trial results on increased risk of major cardiovascular events and cancer

This DHPC is intended to inform healthcare professionals of increased risks of major adverse cardiovascular events and cancer with tofacitinib as compared to tumour necrosis factor inhibitors based on initial results from a recently completed safety clinical trial (A3921133). Xeljanz (tofacitinib) is a medicine for treating adults with moderate to severe rheumatoid arthritis (inflammation of the joints), and psoriatic arthritis (red, scaly patches on the skin with inflammation of the joints). Healthcare professionals should carefully evaluate a patient’s individual benefit-risk profile when deciding to prescribe or continue the treatment. EMA is working closely with the marketing authorisation holder to review the full results of the study and will communicate further once the assessment is completed. 

Eylea: recommendations to mitigate risk of intraocular pressure increase

This DHPC is intended to remind healthcare professionals about the correct handling of Eylea (aflibercept solution for intravitreal injection) pre-filled syringes. Eylea is a medicine used to treat several diseases of the eyes in adults, that is injected into the fluid inside the eye (vitreous humor). A higher-than-expected proportion of cases of increased pressure inside the eye (intraocular pressure) were reported with the Eylea pre-filled syringes. After reviewing the evidence, the PRAC concluded that this may be caused by incorrect handling of the pre-filled Eylea syringes. This DHPC reminds healthcare professionals how to correctly handle pre-filled syringes and the appropriate measures to mitigate this risk.

The DHPCs for Xeljanz and Eylea will be forwarded to EMA’s human medicines committee, the CHMP. Following the CHMP decision, the DHPCs will be disseminated to healthcare professionals by the marketing authorisation holder, according to agreed communication plans, and published on EMA’s website and in National registers in EU Member States.

1Hillaire-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

2Chambord J, Henny F, Salleron J, et al. Ifosfamide‐induced encephalopathy: Brand‐name (HOLOXAN®) vs generic formulation (IFOSFAMIDE EG®). J Clin Pharm Ther. 2019;44:372–380.

3Source: EudraVigilance (data cut-off: 16 February 2021)

Start of referral

Article-20 procedure: Zynteglo

PRAC statistics: March 2021

PRAC statistics: March 2021


  • 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.

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