FDA Approves Terlipressin for the Management of HRS-1

On September 14, 2022, the FDA granted approval to terlipressin (Terlivaz) for the treatment of adults hospitalized with hepatorenal syndrome with rapid reduction in kidney function (HRS-1).¹ Prior to the approval, no approved treatment for this condition existed in the United States. However, terlipressin has been researched and used in the context of HRS-1 for more than 30 years and is often seen as a standard of care outside the United States for this indication.² Terlipressin is a 12–amino acid peptide and vasopressin receptor agonist. A prodrug derived from lysine vasopressin, terlipressin has twice the selectivity for V1 and V2 receptors. Action increases renal perfusion by reducing portal hypertension and shunts splanchnic blood accumulation back to systemic circulation to increase e!ective arterial volume and mean arterial pressure.^3,4

Efficacy

Terlipressin was approved based on results from a randomized, double-blind, placebo-controlled phase 3 registration trial (CONFIRM; NCT02770716) and concurrent resubmission to the FDA in June 2022.^3,5 Participants with HRS-1, cirrhosis, ascites, and rapidly progressing kidney failure (n = 300) were randomly assigned to receive terlipressin at 0.85 mg (n = 199) or placebo (n = 101) every 6 hours for a maximum therapy duration of 14 days.^1,3,5 The primary study end point was the percentage of patients with verified HRS reversal up to day 14 and additionally documented survival without renal replacement therapy for at least 10 days after verified HRS reversal was achieved.^3,5 Verified HRS reversal was defined as 2 consecutive serum creatinine (SCr) values of 1.5 mg/dL or less at least 2 hours apart.⁵

Twenty-nine percent of patients achieved verified HRS reversal with terlipressin vs 16% with placebo (P = .012). A greater percentage of patients in the terlipressin group had an SCr value of 1.5 mg/dL or less while on treatment at day 14 or at discharge and were without renal replacement therapy at day 30 compared with the placebo group (32% vs 16%; P = .003). In a subgroup analysis of those with systemic inflammatory response syndrome, a greater percentage had HRS reversal in the terlipressin group vs placebo group (84% vs 28%; P < .001).^3,5

Safety

Terlipressin safety was also evaluated in the CONFIRM trial. Twelve percent of patients in the terlipressin group discontinued therapy vs 5.1% of the placebo group. The most commonly observed adverse effects (AEs) reported in the treatment arm were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%). Voluntary marketing reports of AEinclude headache, hyponatremia, skin necrosis, and gangrene but do not reflect a causal relationship due to terlipressin exposure.³

Given the incidence of respiratory failure observed in the CONFIRM trial, a warning for serious or fatal respiratory failure exists. Terlipressin is contraindicated in patients experiencing hypoxia or worsening respiratory symptoms and should be discontinued if these occur. Patients should be closely monitored for changes in respiratory status if terlipressin is administered. Terlipressin is also contraindicated in patients with ischemia. If a patient has high priority for a transplant, the benefit of terlipressin is unlikely to outweigh the risk of serious AEs and could lead to ineligibility for liver transplantation.³

Dosing and Administration

Terlipressin is supplied in a single-dose vial containing powder to be reconstituted. An intravenous bolus injection is to be administered over 2 minutes. Terlipressin at 0.85 mg is equivalent to 1 mg of terlipressin acetate. This medication may only be administered in a hospital setting. A dedicated central line is not required for administration.³

Evaluation for renal dose adjustments should occur on the fourth day of therapy. At this time, if the SCr value has decreased by less than 30% from the baseline value, the dose should be increased to 2 mg of terlipressin acetate (equivalent to terlipressin at 1.7 mg) every 6 hours. If the SCr value is equal to or above the baseline value, treatment should be discontinued.^3,5

References

1. FDA approves treatment to improve kidney function in adults with hepatorenal syndrome. FDA. UpdatedSeptember 14, 2022. Accessed December 9, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-improve-kidney-function-adults-hepatorenal-syndrome
2. Mallinckrodt announces resubmission of terlipressin to the FDA for the treatment of hepatorenal syndrome. News release. Mallinckrodt Pharmaceuticals. June 13, 2022. Accessed December 9, 2022. https://www.prnewswire.com/news-releases/mallinckrodt-announces-resubmission-of-terlipressin-to-the-fda-for-the-treatment-of-hepatorenal-syndrome-301565789.html
3. Terlivaz. Prescribing information. Mallinckrodt; 2022. Accessed December 5, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022231s000lbl.pdf
4. Belcher JM, Parada XV, Simonetto DA, et al. Terlipressin and the treatment of hepatorenal syndrome: how the CONFIRM trial moves the story forward. Am J Kidney Dis. 2022;79(5):737-745.doi:10.1053/j.ajkd.2021.08.016
5. 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