Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 30 August – 2 September 2021

News 03/09/2021

COVID-19 vaccines: EMA reviewing cases of multisystem inflammatory syndrome

EMA’s safety committee (PRAC) is assessing whether there is a risk of multisystem inflammatory syndrome (MIS) with COVID-19 vaccines following a report of MIS with Comirnaty. The case occurred in a 17-year old male in Denmark who has since fully recovered.

Some cases of MIS were also reported in the EEA following vaccination with other COVID-19 vaccines.1

MIS is a serious inflammatory condition affecting many parts of the body and symptoms can include tiredness, persistent severe fever, diarrhoea, vomiting, stomach pain, headache, chest pain and difficulty breathing. MIS has previously been reported following COVID-19 disease. The Danish patient, however, had no history of COVID-19.

MIS is rare and its incidence rate before the COVID-19 pandemic estimated from 5 European countries was around 2 to 6 cases per 100,000 per year in children and adolescents below 20 years of age and below 2 cases per 100,000 per year in adults aged 20 years or more.

At this stage, there is no change to the current EU recommendations for the use of COVID-19 vaccines.

The PRAC encourages all healthcare professionals to report any cases of MIS and other adverse events in people having these vaccines.

The PRAC will now assess the available data on MIS to determine whether the condition can be caused by the vaccine and recommend whether any changes to the product information of the vaccines are needed. EMA and national authorities will provide further updates as necessary.

COVID-19 Vaccine Janssen and venous thromboembolism

As part of the ongoing close safety monitoring of the COVID-19 vaccines, PRAC is reviewing data on cases of venous thromboembolism (blood clots in the veins) with COVID-19 Vaccine Janssen.

This safety issue is distinct from the very rare side effect of thrombosis with thrombocytopenia syndrome (TTS) (i.e. blood clots with low blood platelets).  

Venous thromboembolism was included in the risk management plan for COVID-19 Vaccine Janssen as a safety issue to be investigated, based on a higher proportion of cases of venous thromboembolism observed within the vaccinated group versus the placebo group in the first clinical studies used to authorise this vaccine.

PRAC will assess additional data from two large clinical trials of the vaccine, which are to be submitted shortly by the marketing authorisation holder of the vaccine, in order to further evaluate whether the condition is linked to the vaccine.

New safety information for healthcare professionals

As part of its advice on safety-related aspects to other EMA committees, the PRAC discussed a direct healthcare professional communication (DHPC) containing important safety information for Imbruvica.

Imbruvica: new safety signal for use in combination with rituximab and ACE inhibitors

Post-meeting note of 17 September 2021: After the September plenary, the PRAC discussed emerging information and decided that a review of the additional data is needed before advice to healthcare professionals and patients could be provided. A decision on the best tool to communicate the findings of the review and any recommended measures will be taken at a later stage. 

While the assessment is ongoing, healthcare professionals should continue to follow the current product information for Imbruvica. Patients are reminded not to stop taking Imbruvica or ACE inhibitors without first consulting their healthcare professional and to seek medical advice if they have questions or concerns. 

This post-meeting note supersedes the information below.

This DHPC aims to inform healthcare professionals about a new safety signal of sudden or cardiac death with Imbruvica (ibrutinib) when used in combination with rituximab and angiotensin-converting enzyme (ACE) inhibitors. The signal was recognized following a review of the findings of a clinical trial.

Imbruvica is a medicine for treating the blood cancers mantle cell lymphoma, chronic lymphocytic leukaemia (CLL) and Waldenström’s macroglobulinaemia (also known as lymphoplasmacytic lymphoma).

An interim analysis of the clinical trial suggested that the risk of sudden or cardiac death in patients on an ACE inhibitor when entering the study was increased in patients randomised to ibrutinib and rituximab, compared to those randomised to fludarabine, cyclophosphamide and rituximab.

While the PRAC is reviewing the signal, as a precautionary measure, for patients with CLL currently receiving ibrutinib plus rituximab together with an ACE inhibitor, the PRAC advises healthcare professionals to reconsider the treatment strategy.

For patients with CLL on ACE-inhibitors who have not yet started treatment with ibrutinib plus rituximab, the treatment strategy should be reconsidered before commencing ibrutinib.

Patients should not stop taking Imbruvica or ACE inhibitors without first consulting their healthcare professional and should talk to their healthcare professional if they have questions or concerns 2.

The PRAC will communicate final conclusions and recommendations as soon as the evaluation has been completed.

The DHPC for Imbruvica will be forwarded to EMA’s human medicines committee, the CHMP. Following the CHMP decision, the DHPC will be disseminated to healthcare professionals by the marketing authorisation holder, according to an agreed communication plan, and published on EMA’s website and in national registers in EU Member States.

PRAC votes to extend mandate of vice-chair Martin Huber for another three years

The PRAC has voted to prolong, for another three years, the mandate of Dr Martin Huber as vice-chair of the committee. Dr Huber’s new mandate will take effect from October 2021.

1 As of 19 August, cases reported as MIS in children in the EEA from the EudraVigilance database were:

Comirnaty: 5; Spikevax: 1; Vaxzevria: no case; COVID-19 Vaccine Janssen: 1.

Some of the cases occurred in adults rather than in children.

The numbers are likely to change and will be updated as necessary and as the evaluation progresses.

The text was updated on 9 September 2021 to add further advice for patients.

PRAC statistics: September 2021

PRAC statistics: September 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.
  • Pandemic summary safety reports have been introduced as part of the enhanced safety monitoring of COVID-19 vaccines. Marketing authorisation holders are required to submit these reports to EMA on a monthly basis. Their submission complements the submission of PSURs. For more information see EMA’s pharmacovigilance plan for COVID-19 vaccines.

Ongoing referrals




Amfepramone-containing medicinal products - Article -31 ReferralUnder evaluationPRAC continued its assessment

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