Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 7-10 June 2021
PRAC concludes review of signal of capillary leak syndrome with COVID-19 vaccine Vaxzevria
EMA’s safety committee (PRAC) has concluded that people who have previously had capillary leak syndrome must not be vaccinated with Vaxzevria (formerly COVID-19 Vaccine AstraZeneca). The committee also concluded that capillary leak syndrome should be added to the product information as a new side effect of the vaccine, together with a warning to raise awareness among healthcare professionals and patients of this risk.
Capillary leak syndrome is a very rare, serious condition that causes fluid leakage from small blood vessels (capillaries), resulting in swelling mainly in the arms and legs, low blood pressure, thickening of the blood and low blood levels of albumin (an important blood protein).
The committee carried out an in-depth review of six cases of capillary leak syndrome in people who had received Vaxzevria1. Most of the cases occurred in women and within four days of vaccination. Three of those affected had a history of capillary leak syndrome and one of them subsequently died. As of 27 May 2021, more than 78 million doses of Vaxzevria had been administered in the EU/EEA and the UK.2
The PRAC also discussed a direct communication to healthcare professionals to raise awareness of the signs and symptoms of capillary leak syndrome and of its risk of recurrence in people who have previously been diagnosed with the condition (see more information in the dedicated section “New safety information for healthcare professionals”).
The PRAC will continue to monitor for cases of the condition and will take any further actions necessary. For more information see EMA’s public health communication.
1 A total of 14 reports of capillary leak syndrome were reviewed; six had sufficient information for further assessment and were considered to be cases of capillary leak syndrome.
2 EEA: 40.4 million;
UK: 24.3 million first doses and 13.4 million second doses
COVID-19 vaccines: update on ongoing evaluation of myocarditis and pericarditis
The PRAC is continuing its assessment of reports of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the membrane around the heart) in a small number of people following vaccination with COVID-19 vaccines.
The PRAC started its review in April following cases of myocarditis after vaccination with Comirnaty in Israel. Most of these cases were mild and resolved within a few days. They mainly affected males under 30 years of age, with symptoms mostly starting within several days of vaccination with the second dose.
Cases of myocarditis1 and/or pericarditis2 were also reported in the EEA following vaccination with all COVID-19 vaccines.
Currently, further analysis is needed to conclude whether there is a causal relationship with the vaccines, and PRAC is requesting additional data from the companies marketing them.
Myocarditis and pericarditis are inflammatory diseases of the heart that can occur following infections or immune diseases. Depending on the source, the incidence of myocarditis and pericarditis in the EEA ranges from 1 to 10 in 100,000 people per year. Symptoms of myocarditis and pericarditis can vary but often include shortness of breath, a forceful heartbeat that may be irregular, and chest pain. The conditions usually improve on their own or with treatment.
The PRAC encourages all healthcare professionals to report any cases of myocarditis or pericarditis and other adverse events in people having these vaccines. Patients who have symptoms such as shortness of breath, a forceful heartbeat that may be irregular, and chest pain following vaccination should consult their doctor.
For Comirnaty and COVID-19 Vaccine Moderna, the PRAC is reviewing cases of myocarditis and pericarditis in the context of a safety signal, under an accelerated timetable (finalisation expected in July).
For Vaxzevria and COVID-19 Vaccine Janssen, the PRAC is reviewing the cases in the context of the vaccines’ pandemic summary safety reports.
More information is available in EMA’s public health communication.
1 As of end of May 2021, cases of myocarditis reported in the EEA from Eudravigilance database were 122 (Comirnaty), 16 (Covid-19 Vaccine Moderna) and 38 (Vaxzevria) and 0 for Covid-19 Vaccine Janssen. The exposure in the EEA for each vaccine was around 160 million doses for Comirnaty, 19 million doses for Moderna, 40 million for Vaxzevria and 2 million for Janssen.
2 As of end of May 2021, cases of pericarditis reported in the EEA from Eudravigilance database were 126 (Comirnaty), 18 (Covid-19 Vaccine Moderna), 47 (Vaxzevria) and 1 (Covid-19 Vaccine Janssen).
The exposure in the EEA for each vaccine was around 160 million doses for Comirnaty, 19 million doses for Moderna, 40 million for Vaxzevria and 2 million for Janssen.
Conclusion of signal of sinus bradycardia with Veklury
The PRAC has recommended a change to the product information for Veklury (remdesivir) to include sinus bradycardia (heart beats more slowly than usual) as an adverse reaction of unknown frequency for this medicine.
Veklury is an antiviral medicine used to treat COVID-19. It is used in adults and adolescents (from 12 years of age and weighing at least 40 kilograms) with pneumonia requiring supplemental oxygen (low- or high-flow oxygen or other non-invasive ventilation at the start of treatment).
The committee reviewed all the available data on rare reported cases of bradycardia in patients who received Veklury as well as data from clinical trials and the scientific literature. The PRAC concluded that a causal relationship between the use of the medicine and this adverse event is at least a reasonable possibility and recommended a change in the product information to raise awareness among healthcare professionals. The majority of events of sinus bradycardia resolved a few days after the treatment with Veklury was discontinued.
PRAC concludes review of signal of increased risk of major cardiovascular events and cancer with Xeljanz
The PRAC has recommended an update to the product information for Xeljanz to include a new recommendation for its use. The committee has concluded its review of a safety signal regarding major adverse cardiovascular events and cancer (excluding non-melanoma skin cancer). The evidence is gathered from a recent study (A3921133) on this medicine conducted in patients who were 50 years of age or older with at least one additional cardiovascular risk factor. The PRAC is reminding healthcare professionals to carefully evaluate a patient’s individual benefit-risk profile when deciding to prescribe or continue the treatment with Xeljanz. The recommendations are described further in the section below “New safety information for healthcare professionals”.
Xeljanz is used to treat adults with moderate to severe rheumatoid arthritis (inflammation of the joints), psoriatic arthritis (red, scaly patches on the skin with inflammation of the joints) and ulcerative colitis (inflammation and ulcers of the colon and rectum).
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 Vaxzevria and Xeljanz.
Vaxzevria: new contraindication in patients with history of capillary leak syndrome
This DHPC aims to inform healthcare professionals that Vaxzevria is now contraindicated in individuals who have previously experienced episodes of capillary leak syndrome. This follows the review of very rare cases of CLS that have been reported in the first days after vaccination with Vaxzevria.
Xeljanz: new recommendations for use
This DHPC is intended to inform healthcare professionals about the outcome of a signal procedure and new recommendations for use of Xeljanz (tofacitinib).
Final results from a recently completed study (A3921133) showed an increased risk of major adverse cardiovascular events and cancer in some patients, compared with TNF-alpha inhibitors (other medicines for rheumatoid arthritis). The PRAC is therefore advising healthcare professionals that Xeljanz should only be used in patients over 65 years of age, patients who are current or past smokers, patients with other cardiovascular risk factors, and patients with other malignancy risk factors, if no suitable treatment alternative is available.
The DHPCs for Vaxzevria and Xeljanz 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 an agreed communication plan, and published on EMA’s website and in national registers in EU Member States.
- 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.
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