AASLD and ACG recommend terlipressin as the preferred vasoconstrictor therapy for HRS-AKI
AASLD GUIDANCE 20211,a
“The treatment of choice for HRS-AKIb is vasoconstrictor drugs in combination with albumin. The preferred drug is terlipressin.”
ACG GUIDELINES 20222
“In hospitalized patients with cirrhosis and HRS-AKIb without high grade of ACLF or disease, we suggest terlipressin (moderate quality, conditional recommendationc) or norepinephrine (low quality, conditional recommendation) to improve renal function.”
aDiagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Biggins SW, Angeli P, Garcia-Tsao G, Ginès P, Ling SC, Nadim MK, Wong F, Kim WR. Copyright © 2021 American Association for the Study of Liver Diseases. Reproduced with permission of John Wiley & Sons, Inc.
bDefinition of kidney injury for HRS-AKI: increase in SCr of ≥0.3 mg/dL from baseline within 48 hours or percent increase in SCr that is ≥50% of what was known or presumed to have occurred within the prior 7 days.1,2
cIn the ACG guidelines, a strength of recommendation is given as either strong (recommendations) or conditional (suggestions).2
TERLIVAZ is the only FDA‑approved pharmacological treatment for HRS-AKIa
aTERLIVAZ was not evaluated in comparison to other treatments in a head-to-head clinical study.
bNotably, a protocol for norepinephrine use outside of the ICU was implemented at Stanford University. The protocol was restricted to a single inpatient unit that specializes in advanced liver disease and is designated as an “acuity adaptable unit” that can provide intermediate ICU level of care at a 3:1 patient-to-nurse ratio. After failing M&O, norepinephrine is administered as a continuous infusion through a central line, and all patients receive continuous cardiac monitoring. Vanderbilt University has also implemented a protocol for the administration of norepinephrine outside of an ICU setting.13,14
Learn more about where TERLIVAZ was most commonly administered in the CONFIRM trial
SEE THE SETTINGUnderstanding the MOA of TERLIVAZ
See the mechanism of disease for HRS-AKI and how TERLIVAZ is designed to reverse it
TERLIVAZ has a rapid time to onset and long duration of actiona
Pharmacodynamics3
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After a single 0.85-mg dose in patients with HRS, the following was seen within 5 minutes after dose and maintained for at least 6 hours:
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Increase in diastolic, systolic, and MAP
- Max change in blood pressure and heart rate: 1.2 to 2 hours post dose
- MAP: estimated maximum effect = increase of 16.2 mmHg
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Decrease in heart rate
- Estimated maximum effect for heart rate = decrease of 10.6 beats/min
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Pharmacokinetics3
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Terminal half-life
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TERLIVAZ: 0.9 hours
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Lysine-vasopressin: 3 hours
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aOther pharmacological therapies currently utilized for the treatment of HRS have half-lives ranging from ~2.4 minutes to 4 hours.4-7
AASLD, American Association for the Study of Liver Diseases; ACG, American College of Gastroenterology; ACLF, acute-on-chronic liver failure; HRS-AKI, hepatorenal syndrome–acute kidney injury; ICU, intensive care unit; MAP, mean arterial pressure; MOA, mechanism of action; PD, pharmacodynamic; PK, pharmacokinetic; SCr, serum creatinine.
IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS OR FATAL RESPIRATORY FAILURE
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TERLIVAZ® may cause serious or fatal respiratory failure. Patients with volume overload or with acute-on-chronic liver failure (ACLF) Grade 3 are at increased risk. Assess oxygenation saturation (e.g., SpO2) before initiating TERLIVAZ.
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Do not initiate TERLIVAZ in patients experiencing hypoxia (e.g., SpO2 <90%) until oxygenation levels improve. Monitor patients for hypoxia using continuous pulse oximetry during treatment and discontinue TERLIVAZ if SpO2 decreases below 90%.
INDICATION AND LIMITATION OF USE
TERLIVAZ is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.
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Patients with a serum creatinine >5 mg/dL are unlikely to experience benefit.
CONTRAINDICATIONS
TERLIVAZ is contraindicated:
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In patients experiencing hypoxia or worsening respiratory symptoms.
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In patients with ongoing coronary, peripheral, or mesenteric ischemia.
Warnings and Precautions
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Serious or Fatal Respiratory Failure: Obtain baseline oxygen saturation and do not initiate TERLIVAZ in hypoxic patients. Monitor patients for changes in respiratory status using continuous pulse oximetry and regular clinical assessments. Discontinue TERLIVAZ in patients experiencing hypoxia or increased respiratory symptoms.
Manage intravascular volume overload by reducing or discontinuing the administration of albumin and/or other fluids and through judicious use of diuretics. Temporarily interrupt, reduce, or discontinue TERLIVAZ treatment until patient volume status improves. Avoid use in patients with ACLF Grade 3 because they are at significant risk for respiratory failure.
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Ineligibility for Liver Transplant: TERLIVAZ-related adverse reactions (respiratory failure, ischemia) may make a patient ineligible for liver transplantation, if listed. For patients with high prioritization for liver transplantation (e.g., MELD ≥35), the benefits of TERLIVAZ may not outweigh its risks.
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Ischemic Events: TERLIVAZ may cause cardiac, cerebrovascular, peripheral, or mesenteric ischemia. Avoid use of TERLIVAZ in patients with a history of severe cardiovascular conditions or cerebrovascular or ischemic disease. Discontinue TERLIVAZ in patients who experience signs or symptoms suggestive of ischemic adverse reactions.
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Embryo-Fetal Toxicity: TERLIVAZ may cause fetal harm when administered to a pregnant woman. If TERLIVAZ is used during pregnancy, the patient should be informed of the potential risk to the fetus.
Adverse Reactions
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The most common adverse reactions (≥10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea.
Please see full Prescribing Information, including Boxed Warning.
References: 1. Biggins SW, Angeli P, Garcia-Tsao G, et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;74(2):1014-1048. doi:10.1002/hep.31884 2. Bajaj JS, O’Leary JG, Lai JC, et al. Acute-on-chronic liver failure clinical guidelines. Am J Gastroenterol. 2022;117(2):225-252. doi:10.14309/ajg.0000000000001595 3. TERLIVAZ® (terlipressin). Prescribing Information. Bridgewater, NJ: Mallinckrodt Hospital Products Inc. 4. LEVOPHED® (norepinephrine bitartrate). Prescribing information. Hospira, Inc; 2020. 5. Midodrine hydrochloride. Prescribing information. Mylan Pharmaceuticals Inc; 2022. 6. Sandostatin® (octreotide acetate). Prescribing information. Novartis Pharmaceuticals Corporation; 2023. 7. Vasostrict® (vasopressin injection). Prescribing information. Par Pharmaceuticals Companies, Inc; 2023. 8. Karvellas CJ, Subramanian R, Olson JC, Jamil K. Role of terlipressin in patients with hepatorenal syndrome-acute kidney injury admitted to the ICU: a substudy of the CONFIRM trial. Crit Care Explor. 2023;5(4):e0890. doi:10.1097/CCE.0000000000000890 9. Tariq R, Singal AK. Management of hepatorenal syndrome: a review. J Clin Transl Hepatol. 2020;8(2):192-199. doi:10.14218/JCTH.2020.00011 10. Lizaola-Mayo B, Vargas HE. Hepatorenal syndrome-acute kidney injury in liver transplantation. Clin Gastroenterol Hepatol. 2023;21(10S):S20-S26. doi:10.1016/j.cgh.2023.06.010 11. Mattos AZ, Schacher FC, Mattos AA. Vasoconstrictors in hepatorenal syndrome: a critical review. Ann Hepatol. 2019;18(2):287-290. doi:10.1016/j.aohep.2018.12.002 12. Gordan R, Gwathmey JK, Xie LH. Autonomic and endocrine control of cardiovascular function. World J Cardiol. 2015;7(4):204-214. doi:10.4330/wjc.v7.i4.204 13. Kwong A, Kim WR, Kwo PY, Wang U, Cheng X. Feasibility and effectiveness of norepinephrine outside the intensive care setting for treatment of hepatorenal syndrome. Liver Transpl. 2021;27(8):1095-1105. doi:10.1002/lt.26065 14. Backhaus K, Connell J, Belfi AC, Shingina A. Effectiveness of norepinephrine infusion protocol in achieving the resolution of hepatorenal syndrome. Gastroenterology. 2023;164(suppl 6):S1320. American Association for the Study of Liver Diseases abstract Su1536.