Terlipressin-containing medicinal products indicated in the treatment of hepatorenal syndrome

  • Procedure started
  • Under evaluation
  • PRAC recommendation
  • CMDh final position
Current status
CMDh final position

Overview

New recommendations for terlipressin-containing medicines in the treatment of hepatorenal syndrome

On 29 September 2022, EMA’s safety committee (PRAC) recommended new measures to reduce the risk of respiratory failure (severe breathing difficulties that may be life-threatening) and sepsis (when bacteria and their toxins circulate in the blood, leading to organ damage) when using terlipressin-containing medicines in people with type 1 hepatorenal syndrome (type 1 HRS) (serious kidney problems in people with advanced liver disease). 

The new measures include adding to the product information a warning to avoid using terlipressin-containing medicines in patients with advanced acute-on-chronic liver disease (liver disease that suddenly worsens) or advanced kidney failure. Patients with breathing problems should receive treatment to manage their condition before starting terlipressin-containing medicines. During and after treatment, patients should be monitored for signs and symptoms of respiratory failure and infection.

In addition, healthcare professionals can consider giving terlipressin-containing medicines as a continuous infusion (drip) into the vein as an alternative to giving it by bolus injection (full dose injected in one go) as this may reduce the risk of severe side effects1.

The recommendations follow the PRAC’s review of available data, including results from a clinical trial2 involving patients with type 1 HRS which suggested that patients who were treated with terlipressin-containing medicines were more likely to experience and die from respiratory disorders within 90 days after the first dose than those who were given placebo (a dummy treatment).

Although respiratory failure is a known side effect of terlipressin-containing medicines, the frequency of respiratory failure seen in the study was higher (11%) than previously reported in the product information. In addition, the study reported sepsis in 7% of patients in the terlipressin arm compared with none in the placebo group.

There were limitations to the data, such as differences in how terlipressin was used in the clinical trials compared to clinical practice. After considering these limitations together with other available data and consulting an expert group composed of healthcare professionals with expertise in the field of hepatorenal syndrome, PRAC concluded that new measures were needed to ensure that the benefits of terlipressin-containing medicines continue to outweigh the risks.

The PRAC recommendations were sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) which endorsed them and adopted its position on 10 November 2022.


1 Cavallin M, Piano S, Romano A, et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study. Hepatology. 2016;63(3):983-92. doi:10.1002/hep.28396

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

Key facts

About this medicine
Approved name
Terlipressin-containing medicinal products indicated in the treatment of hepatorenal syndrome
International non-proprietary name (INN) or common name
terlipressin
Class
vasopressin and analogues
About this procedure
Current status
CMDh final position
Reference number
EMEA/H/A-31/1514
Type
Article 31 referrals

This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Authorisation model
Nationally authorised product(s)
Decision making model
PRAC-CMDh
Key dates and outcomes
Procedure start date
13/01/2022
PRAC recommendation date
29/09/2022
CHMP opinion/CMDh position date
10/11/2022

All documents

Procedure started

Under evaluation

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Position provided by CMDh

  • List item

    Terlipressin-containing medicinal products Article-31 referral - New recommendations for terlipressin-containing medicines in the treatment of hepatorenal syndrome (PDF/122.11 KB)


    First published: 11/11/2022
    Last updated: 22/12/2022
    EMA/862470/2022

  • List item

    Terlipressin-containing medicinal products Article-31 referral - Annex VI (PDF/79.59 KB)


    First published: 22/12/2022

  • List item

    Terlipressin-containing medicinal products Article-31 referral - Annex II (PDF/154 KB)


    First published: 22/12/2022

  • List item

    Terlipressin-containing medicinal products Article-31 referral - Annex I (PDF/154.81 KB)


    First published: 22/12/2022

  • List item

    Terlipressin-containing medicinal products Article-31 referral - PRAC assessment report (PDF/2.38 MB)

    Adopted

    First published: 18/11/2022
    EMA/885651/2022

  • List item

    Terlipressin-containing medicinal products Article-31 referral - New recommendations for terlipressin-containing medicines in the treatment of hepatorenal syndrome (PDF/122.11 KB)


    First published: 11/11/2022
    Last updated: 22/12/2022
    EMA/862470/2022

  • List item

    Terlipressin-containing medicinal products Article-31 referral - Timetable for the implementation of the CMDh position (PDF/69.57 KB)


    First published: 11/11/2022

  • List item

    Terlipressin-containing medicinal products Article-31 referral - Annex III (PDF/162.5 KB)


    First published: 11/11/2022
    Last updated: 22/12/2022

  • Description of documents published

    Please note that some of the listed documents apply only to certain procedures.

    • Overview - lay-language summary of the stage of the procedure
    • Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
    • Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
    • List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
    • Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
    • List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
    • List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
    • Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
    • Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
    • Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
    • Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
    • Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
    • Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
    • Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
    • Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

    Note that older documents may have different titles.

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