Product Overview

Terlipressin (Glypressin^®) is a vasopressin analogue indicated for the treatment of type 1 hepatorenal syndrome (HRS), characterised by spontaneous acute renal insufficiency in patients suffering from severe cirrhosis with ascites. It is also indicated for the treatment of bleeding oesophageal varices.

At present, there are two (2) terlipressin-containing products registered with the Drug Control Authority (DCA) in Malaysia.

Background of the Safety Issue

The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) has finished reviewing the safety of terlipressin in the treatment of type 1 HRS, following new information from the CONFIRM trial. The PRAC concluded that there is a need for updating the package insert and issuing a communication letter to healthcare professionals to mitigate the risk of respiratory failure and sepsis/septic shock when using terlipressin in patients with type 1 HRS treatment.

New findings from the CONFIRM trial have shown that the use of terlipressin plus albumin effectively reverses HRS (p = .006). However, it was observed that 11% of patients receiving terlipressin plus albumin died within 90 days due to respiratory disorders, as compared with 2% of patient receiving placebo plus albumin. Although the respiratory failure being a known side effect of terlipressin, the frequency of respiratory failure observed in the terlipressin group was higher than that reported in the package insert. Furthermore, there was an increased risk of sepsis/septic shock in patients with type 1 HRS who received terlipressin versus none in the placebo group.

Apart from that, certain clinical trials have observed reduced efficacy, increased mortality, and increased risks of serious adverse events when terlipressin is used for the treatment of type 1 HRS in patients with advanced renal dysfunction (baseline serum creatinine ≥ 442µmol/l [5 mg/dl]) and in patients with Acute-on-Chronic Liver Failure (ACLF) grade 3. Notably, patients with ACLF grade 3 and/or Model for End-Stage Liver Disease (MELD) score ≥ 39 are particularly at increased risk of developing respiratory failure.

Additionally, data from other trial (Cavallin et al., 2016) suggests that continuous intravenous (IV) infusion of terlipressin may have lower rates of treatment-related adverse events than IV bolus injection.

Advice for Health Care Professionals:

• Be aware that new findings from clinical trials have indicated:
  • a higher frequency of serious or fatal respiratory failure than previously documented;
  • an increased risk of sepsis/septic shock in patients treated for Type 1 HRS with terlipressin.
• Unless the benefits outweigh the risks, avoid using terlipressin in patients with the following conditions:
  • Advanced renal dysfunction (baseline serum creatinine ≥ 442 µmol/l [5 mg/dl]);
  • Acute-on-Chronic Liver Failure (ACLF) grade 3 and/or Model for End-Stage Liver Disease (MELD) score ≥ 39.
• Prior to administering the first dose of terlipressin, stabilise patients with new onset of breathing difficulties or worsening of existing respiratory disease.
• Administer terlipressin through continuous intravenous infusion rather than bolus injection to minimise adverse events.
• When terlipressin and albumin are administered concurrently, consider reducing the human albumin dose if patients develop respiratory symptoms. However, in cases of severe or unresolved symptoms, discontinue terlipressin treatment.
• Monitor patients closely throughout the treatment period and watch for signs and symptoms of infection.

The local packet insert for Glypressin^® (terlipressin) is being updated to include new information on the increased risk of serious or fatal respiratory failure and sepsis/septic shock and recommendations to minimise the risk of developing adverse events associated with bolus injection.

On 11^th April 2023, the NPRA had approved a Direct Healthcare Professional Communication (DHPC) letter to be distributed by Ferring Sdn. Bhd. to highlight these safety issues associated with terlipressin use for Type 1 HRS. For further information, please contact your local salesperson for a copy of the DHPC.

Reference:

Direct Healthcare Professional Communication (DHPC). Glypressin® (terlipressin): Serious or fatal respiratory failure and sepsis/septic shock in patients with type 1 hepatorenal syndrome (type 1 HRS). Ferring Sdn Bhd; 2023 Apr 11.

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.