Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 10 - 13 January 2022

News 14/01/2022

Review of terlipressin medicines started

EMA has started a review of medicines that contain terlipressin. These medicines are authorised in several EU countries to treat increased pressure in central veins causing kidney problems in people with advanced liver disease (hepatorenal syndrome; HRS), as well as bleeding from enlarged veins in the passage between the mouth and the stomach (the oesophagus) and certain forms of bleeding associated with surgery. 

EMA’s safety committee (PRAC) started this review due to safety concerns about results from a large clinical trial1 involving patients with a form of HRS where kidney function declines rapidly.

As a result of these concerns, the Danish medicines agency requested a review of the safety of terlipressin medicines in the context of their benefits when used to treat HRS. At present, this review does not cover the use of terlipressin for the treatment of bleeding, since no new information on safety concerns has emerged for these uses.

More information is available in EMA’s public health communication.

Vaxzevria and COVID-19 Vaccine Janssen: update on very rare cases of transverse myelitis

The PRAC has recommended a change to the product information for Vaxzevria and COVID-19 Vaccine Janssen to include a warning to raise awareness among healthcare professionals and people receiving the vaccines of very rare cases of transverse myelitis (TM) reported following vaccination. TM has also been added as an adverse reaction of unknown frequency.

TM is a rare neurological condition characterised by an inflammation of one or both sides of the spinal cord. It can cause weakness in the arms or legs, sensory symptoms (such as tingling, numbness, pain or loss of pain sensation) or problems with bladder or bowel function.

The Committee has reviewed available information on globally reported cases, including those in the European database for suspected side effects (EudraVigilance) and data from the scientific literature, with both vaccines2. The PRAC has concluded that a causal relationship between these two vaccines and transverse myelitis is at least a reasonable possibility. The benefit-risk profile of both vaccines remains unchanged.

Healthcare professionals should be alert to signs and symptoms of TM, allowing early diagnosis, supportive care and treatment. People receiving either of these vaccines are advised to seek immediate medical attention if they develop symptoms of the condition.

EMA will continue to closely monitor this issue and will communicate further if new information becomes available.

Vaxzevria: fewer cases of thrombosis with thrombocytopenia reported after second dose

The PRAC has recommended updating the product information for Vaxzevria to add more information about the very rare cases of thrombosis with thrombocytopenia (TTS) that occurred following vaccination.

A review of cumulative data has highlighted that the majority of suspected TTS events were reported worldwide after the administration of the first dose. Fewer events have been observed after the second dose. In fact, out of 1,809 thromboembolic events with thrombocytopenia reported worldwide, 1,643 were reported after the first dose and 166 after the second dose.

As per the current product information, the administration of a second dose of Vaxzevria is contraindicated in people who have experienced TTS following vaccination with this vaccine.

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 communication (DHPC) containing important safety information for Mavenclad.

Mavenclad: risk of serious liver injury

This DHPC aims to inform healthcare professionals about adverse events of liver injury with Mavenclad (cladribine), and gives new recommendations about liver function monitoring.

Mavenclad is a medicine used to treat adults with the relapsing forms (repeated flare-ups of the symptoms) of multiple sclerosis, a disease in which inflammation damages the protective sheath around the nerve cells in the brain and spinal cord (demyelination). Mavenclad is used in patients whose disease is highly active.

Liver injury, including serious cases and cases leading to discontinuation of treatment, has been reported in patients treated with Mavenclad. A recent review of available safety data has concluded on an increased risk for liver injury following treatment with Mavenclad. Most patients who experienced liver injury had mild clinical symptoms. However, in some cases, transitory high levels of enzyme transaminase exceeding 1000 units per litre and jaundice (liver affection causing, amongst others, yellowing of the skin and eyes) were described.

Liver injury will be included in the product information of Mavenclad as an adverse drug reaction of uncommon frequency.

Healthcare professionals are advised to perform a detailed review of patient history of underlying liver disorders or episodes of liver injury with other medicines before initiating patient treatment. During treatment, liver function tests should be conducted, and repeated as necessary. In case a patient develops liver injury, treatment with Mavenclad should be interrupted or discontinued, as appropriate.

Patients should be advised to report immediately to their healthcare professional any signs or symptoms of liver injury. Healthcare professionals are asked to report any suspected adverse reactions via their national reporting system. Reporting suspected adverse reactions after authorisation of the medicinal product is important to ensure patient safety.

The DHPC for Mavenclad 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 the Direct healthcare professional communications page and in national registers in EU Member States.

1 Wong F, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med. 2021 Mar 4;384(9):818-828. doi: 10.1056/NEJMoa2008290

2 In total, 38 globally reported cases were considered, 25 cases with Vaxzevria and 13 with COVID-19 Vaccine Janssen. Respectively, global exposure to the vaccines was estimated at 1,391 billion doses for Vaxzevria and at 33,584,049 for COVID-19 Vaccine Janssen. These numbers refer to suspected and not adjudicated cases of TM.

PRAC statistics: January 2022

PRAC highlights January 2022 figures


  • 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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