Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 25-28 October 2021

News 29/10/2021

PRAC assessing further data on risk of myocarditis and pericarditis with mRNA vaccines

EMA’s safety committee (PRAC) is assessing further data providing more information on the risk of myocarditis and pericarditis following vaccination with COVID-19 vaccines Comirnaty and Spikevax (previously COVID-19 Vaccine Moderna).

Myocarditis and pericarditis are inflammatory conditions of the heart. Symptoms can vary but often include breathlessness, a forceful heartbeat that may be irregular (palpitations), and chest pain.

The PRAC had previously reviewed cases of myocarditis and pericarditis spontaneously reported in the European Economic Area (EEA). The review concluded in July 2021 with a recommendation to list both conditions as side effects in the product information for these vaccines, together with a warning to raise awareness among healthcare professionals and people getting these vaccines.

The committee has now asked the companies that market these vaccines to perform an in-depth review of all published data on the association of myocarditis and pericarditis, including clinical trial data, data from the literature and data available in the public domain.

EMA will continue to monitor the vaccines’ safety and effectiveness and will communicate further when new information becomes available.

COVID-19 vaccines: PRAC finds insufficient evidence on a possible link with multisystem inflammatory syndrome

The PRAC has concluded that there is currently insufficient evidence on a possible link between COVID-19 vaccines and very rare cases of multisystem inflammatory syndrome (MIS).

MIS is a rare 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 committee’s assessment is based on the available spontaneous reports and currently does not warrant an update of the product information.

The PRAC encourages all healthcare professionals to report any cases of MIS that may have occurred after vaccination and other adverse events in people receiving these vaccines.

EMA will continue to closely monitor any new reports of the condition and take appropriate measures if necessary.

PRAC starts review of signal of capillary leak syndrome with Spikevax

The PRAC has started a review of a safety signal to assess reports of capillary leak syndrome in people who were vaccinated with Spikevax.

Six cases of this very rare disorder, characterised by leakage of fluid from blood vessels causing tissue swelling and a fall in blood pressure, were reported in the EudraVigilance database. At this stage, it is not yet clear whether there is a causal association between vaccination and the reports of capillary leak syndrome.

These reports point to a ‘safety signal’ - information on new or changes in adverse events that may potentially be associated with a medicine and that warrant further investigation, especially in the population with a medical history of this condition.

The 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 is necessary in order to minimise the risk. This usually results in an update of the summary of product characteristics and the package leaflet.

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

Imbruvica: risk of sudden or cardiac death not linked to concomitant use of ACE inhibitors

The PRAC has concluded the review of a safety signal of sudden or cardiac death with Imbruvica (ibrutinib) when used in combination with angiotensin-converting enzyme (ACE) inhibitors.

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).

Interim data from a clinical trial suggested that the risk of sudden or cardiac death in patients on an ACE inhibitor when entering the study may be increased in patients randomised to ibrutinib and rituximab, compared to those randomised to fludarabine, cyclophosphamide and rituximab.

After reviewing additional analyses from different sources including other clinical trials, the PRAC has concluded that the possible association between treatment with Imbruvica with concomitant use of ACE inhibitors and the risk of sudden or cardiac death does not seem to be plausible.

Among the patients enrolled in the clinical trials sponsored by the marketing authorisation holder, there were no statistically significant differences in events of sudden or cardiac death between those treated with ACE inhibitors and Imbruvica, and those who received ACE inhibitors and a comparator.

The committee has therefore decided that although some cardiac adverse reactions are already known for Imbruvica, a further analysis of serious cardiac events is considered necessary in order to determine if these events might be linked to the use of Imbruvica alone and better characterise the risk of cardiotoxicity with the medicine, regardless of ACE inhibitor use.

The further review will be performed through a separate regulatory procedure, therefore this signal procedure is closed.

PRAC statistics: November 2021

PRAC statistics: September 2021


  • Safety signal assessments. A safety signal is information which suggests a new potentially causal association, or a new aspect of a known association between a medicine and an adverse event that warrants further investigation. Safety 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 'Periodic safety update reports: questions and answers'.
  • 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'.
  • 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.
  • 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.
Nomegestrol and chlormadinone - Article - 31 ReferralUnder evaluationPRAC continued its assessment.


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