Terlipressin: new recommendations to reduce risks of respiratory failure and septic shock in patients with type 1 hepatorenal syndrome

New recommendations following a recent clinical trial which found that in patients with type 1 hepatorenal syndrome terlipressin may cause serious or fatal respiratory failure at a frequency higher than previously known, and that terlipressin increases the risk of sepsis and septic shock.

From:
Medicines and Healthcare products Regulatory Agency
Published
23 March 2023

Consider the individual benefits and risks for patients with type 1 hepatorenal syndrome when initiating terlipressin treatment, especially for those with severe renal or hepatic impairment and monitor all patients closely during terlipressin treatment. This advice is not relevant to use of terlipressin for bleeding oesophageal varices.

Advice for healthcare professionals:

  • findings of the CONFIRM trial showed terlipressin to be effective at reversing type 1 hepatorenal syndrome, but also showed that patients who received terlipressin were more likely to die by day 90 (largely due to respiratory disorders) than those who received placebo
  • there were also more serious respiratory events and cases of sepsis or septic shock in patients who received terlipressin than in those who received placebo
  • since both advanced renal impairment and advanced liver impairment were risk factors for poorer outcomes in patients with type 1 hepatorenal syndrome:
    • avoid terlipressin in those with advanced renal dysfunction (baseline serum creatinine at or above 442 µmol/L (5.0 mg/dL)), unless the benefit is judged to outweigh the risks
    • avoid terlipressin in those with severe liver disease (defined as Acute-on-Chronic Liver Failure (ACLF) grade 3, a Model for End-stage Liver Disease (MELD) score ≥ 39, or both), unless the benefit is judged to outweigh the risks
  • stabilise patients with new-onset breathing difficulties or worsening of existing respiratory disease before administering terlipressin and monitor closely during treatment
  • consider a reduction in albumin dose in patients with signs or symptoms of respiratory failure or fluid overload; discontinue terlipressin if symptoms are severe or do not resolve
  • monitor patients daily for signs and symptoms of infection
  • monitor blood pressure, heart rate, oxygen saturation, serum sodium and potassium levels, and fluid balance; terlipressin may induce myocardial ischaemia and pulmonary vascular congestion, especially in those with pre-existing cardiopulmonary disease
  • terlipressin can be administered as a continuous intravenous infusion as an alternative to bolus injection as infusion may be associated with lower rates of severe adverse events than bolus injection
  • patients with type 1 hepatorenal syndrome receiving terlipressin should be counselled on the benefits and risks, even if circumstance necessitates that counselling occurs after treatment with terlipressin is given
  • this advice is not relevant to use of terlipressin for bleeding oesophageal varices
  • report suspected adverse drug reactions associated with terlipressin on a Yellow Card

Advice for healthcare professions to provide to patients, as well as families and caregivers:

  • terlipressin can be used in hospitals for emergency treatment of type 1 hepatorenal syndrome, a life-threatening type of kidney failure in patients with severely impaired liver function
  • terlipressin has been linked to breathing difficulties and blood infections when used to treat patients for type 1 hepatorenal syndrome – healthcare professionals will monitor patients receiving terlipressin closely for these risks
  • since patients with very severe liver or kidney disease are thought to be at particular risk, we have recommended that these patients should only receive terlipressin if their prescriber feels that the benefits to them outweigh the potential risks
  • patients with concerns about their medicines should talk to their healthcare professional
  • this advice is not relevant to use of terlipressin for bleeding from dilated veins in the food pipe leading to the stomach (bleeding oesophageal varices)

About terlipressin

Terlipressin is a synthetic pituitary hormone. It is authorised for treatment of bleeding from dilated veins in the food pipe leading to the stomach (bleeding oesophageal varices) and for emergency treatment of type 1 hepatorenal syndrome (rapidly progressive renal failure in patients with liver cirrhosis (scarring of the liver) and ascites (fluid accumulation in the abdomen)). The advice in this article relates only to use of terlipressin for type 1 hepatorenal syndrome.

Terlipressin acts as a vasopressin analogue that works by reducing portal venous pressure in the liver, in patients with portal hypertension, and also contributes to improved blood circulation in the kidney helping to restore renal function.

Findings of the CONFIRM trial

The CONFIRM trial[footnote 1]: was a phase 3 clinical trial conducted in the USA and Canada, comparing the efficacy of terlipressin plus albumin with that of placebo plus albumin in the treatment of type 1 hepatorenal syndrome. A total of 300 patients underwent randomisation — 199 were assigned to the terlipressin group and 101 to the placebo group.

The primary endpoint of the CONFIRM trial was verified reversal of type 1 hepatorenal syndrome. The study showed that the proportion of patients who had verified reversal of hepatorenal syndrome was significantly higher in the terlipressin group than in the placebo group (63 patients (32%) versus 17 patients (17%); p=0.0006).

Mortality up to 90 days was measured as a secondary outcome. By day 90, deaths had occurred in 101 patients (51%) in the terlipressin group and in 45 patients (45%) in the placebo group. The increased mortality at 90 days in the terlipressin group was driven by respiratory disorders, with 22 deaths (11%) due to respiratory disorders in the terlipressin group and 2 deaths (2%) in the placebo group.

The most commonly reported respiratory adverse events in the terlipressin group were respiratory failure, dyspnoea, and pulmonary oedema. These events were reported at a higher frequency than is currently indicated in the product information. The frequency of these events is now evaluated as very common for respiratory failure and dyspnoea and common for pulmonary oedema.

Furthermore, in the time period up to 30 days after the end of treatment, cases of respiratory failure and acute respiratory failure were higher in the terlipressin group than in the placebo group (20 patients (10%) versus 3 patients (3%) for respiratory failure; 8 patients (4%) versus 2 patients (2%), respectively, for acute respiratory failure).

There were also more cases of sepsis; with 14 patients (7%) in the terlipressin group experiencing serious adverse events (SAEs) related to sepsis and septic shock versus none in the placebo group. Eight of these 14 patients who developed sepsis or septic shock in the terlipressin group died due to the event.

Recent review of benefits and risks

A recent European review into the benefits and risks of terlipressin treatment, which was triggered by the CONFIRM trial findings, concluded that new measures were required to reduce the risk of respiratory failure and sepsis when terlipressin is used in patients with type 1 hepatorenal syndrome. The Pharmacovigilance Expert Advisory Group of the UK’s Commission on Human Medicines agreed with the recommendations, while also highlighting the benefits of terlipressin treatment when an appropriate assessment of the benefits and risks has been made.

Changes will therefore be made to the product information for terlipressin medicines authorised for type 1 hepatorenal syndrome to note the new risk minimisation measures and information on risks. A letter has also been sent to UK healthcare professionals.

Risk factors

The review confirmed that terlipressin remains a highly effective treatment for type 1 hepatorenal syndrome but identified some risk factors that should be considered by prescribers when treatment decisions are made.

The review identified patients with severe renal impairment (in this review, defined as patients with baseline serum creatinine above 5 mg/dl) as being at reduced likelihood of response to terlipressin as well as at increased risk of death. A post-hoc subgroup analysis of the CONFIRM trial identified patients with severe renal impairment (in this review, defined as patients with baseline serum creatinine above 5 mg/dl) and severe reduction in liver function (in particular patients with ACLF grade 3 or a MELD score ≥ 39) as having a reduced likelihood of response to terlipressin as well as an increased risk of developing respiratory failure and fluid-overload-related serious adverse events and of death.

An assessment of benefits and risks for the individual patient should be made when deciding on appropriate treatment in patients with these risk factors.

It was acknowledged that the doses of albumin given in the CONFIRM trial were higher than would usually be advised in European guidelines and this may have contributed to fluid overload and the respiratory events seen. The dose of albumin should therefore be considered if signs of respiratory failure or fluid overload arise.

Method of administration

Continuous infusion has been added to the product information as an alternative method of administration to bolus injection.

Continuous infusion has been recommended within the European Association for the Study of the Liver (EASL) guidelines for some time and a small amount of literature suggests that this method is associated with a better safety profile and has a more stable lowering effect on portal pressure than bolus administration by avoiding high peak plasma concentrations of terlipressin. While the literature is insufficient to suggest that continuous infusion would lower the rate of respiratory events specifically, the evidence is sufficient to recommend this as an alternative method of administration.

Report suspected reactions on a Yellow Card

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting suspected adverse drug reactions, please provide as much information as possible, including information about medical history, any concomitant medication, onset timing, and treatment dates. When reporting for a biological medicine or vaccine, please ensure that you provide the brand name (or product licence number and manufacturer), and the specific batch number.

Article citation: Drug Safety Update volume 16, issue 8: March 2023: 2.

  1. Wong F and others. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. New England Journal of Medicine 2021; volume 384, pages 818 to 828. ↩

Published 23 March 2023
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