Peptide education
Terlipressin
Terlivaz · Terlipressin acetate
Terlipressin is a vasopressin analog used to improve kidney function in adults with hepatorenal syndrome and rapidly declining kidney function. The US product Terlivaz is given intravenously and carries a boxed warning for serious or fatal respiratory failure.
In CONFIRM, the published analysis reported verified kidney-response reversal of 32% with terlipressin and 17% with placebo, including imputation for some missing outcomes. The US label reports 29.1% and 15.8% and warns of serious or fatal respiratory failure.
Overview
Quick answer
A kidney-function response does not necessarily mean better survival. CONFIRM found more verified hepatorenal-syndrome reversals with terlipressin, but respiratory complications were also more frequent.
What is terlipressin used for?
The US label covers adults with hepatorenal syndrome and a rapid reduction in kidney function. The label says patients with serum creatinine above 5 mg/dL are unlikely to experience benefit.
What did CONFIRM show?
The published analysis reported verified reversal of 63/199 with terlipressin versus 17/101 with placebo, using imputation for some missing outcomes. Concomitant albumin was strongly recommended in both groups. The study did not establish a survival advantage.
Why do the trial and label report different response counts?
The published analysis lists 63 versus 17 and used a modified success definition and multiple imputation for missing outcomes. The label lists 58 versus 16 and describes qualifying creatinine measurements while on treatment. Both require two readings at or below 1.5 mg/dL at least 2 hours apart and at least 10 days alive without renal replacement therapy. The publication describes those 10 days after treatment completion; the label describes them after reversal. The exact reasons for all count differences are not established by these descriptions alone.
What are the most serious risks?
Serious or fatal respiratory failure is the boxed warning. The label also contraindicates use in patients with hypoxia or worsening respiratory symptoms, or with ongoing coronary, peripheral or mesenteric ischemia. It advises avoiding use in grade 3 acute-on-chronic liver failure.
Why do some sources say 1 mg and others say 0.85 mg?
One Terlivaz vial contains 0.85 mg of terlipressin, equivalent to 1 mg of terlipressin acetate. These are base and salt expressions of the same amount in that product, not two separate starting doses.
Evidence
Evidence snapshot
Terlivaz is indicated to improve kidney function in adults with hepatorenal syndrome and rapid kidney-function decline. Patients with serum creatinine above 5 mg/dL are unlikely to benefit, according to the label.
The publication reported 63/199 with terlipressin and 17/101 with placebo for verified reversal, including imputation for some missing outcomes. Concomitant albumin was strongly recommended in both groups.
The prescribing information reports 58 of 199 terlipressin patients and 16 of 101 placebo patients with verified reversal. These counts differ from the published report.
The label reports serious or fatal respiratory failure in 14% of treated patients versus 5% of placebo patients in the primary trial.
The published trial reported death by day 90 in 51% of the terlipressin group and 45% of the placebo group. A kidney response does not establish a survival benefit.
Claims
Common claims vs evidence
| Claim | Human evidence | Mechanistic evidence | Verdict |
|---|---|---|---|
| Terlipressin improves kidney function in some patients with HRS. | CONFIRM compared terlipressin with placebo in adults with cirrhosis and rapidly progressive type 1 hepatorenal syndrome. The publication and US label reported higher verified-reversal results with terlipressin, using different analysis descriptions. | Terlipressin acts on vasopressin receptors and is also converted to lysine-vasopressin. Its effects on circulation are thought to increase kidney blood flow in hepatorenal syndrome. | Supported for the defined kidney-response endpoint in the studied population. Response does not eliminate the underlying liver disease. |
| Kidney-function reversal proves a survival benefit. | The published trial reported 90-day deaths in 101 of 199 terlipressin patients and 45 of 101 placebo patients. More respiratory-related deaths occurred in the terlipressin group. | The trial did not establish that kidney response produces longer survival. | |
| Respiratory failure is a minor precaution. | The US label carries a boxed warning for serious or fatal respiratory failure. It identifies volume overload and grade 3 acute-on-chronic liver failure as factors associated with increased risk and advises avoiding use with grade 3 acute-on-chronic liver failure. | Respiratory status and patient selection are central to treatment. The label contraindicates use in patients with hypoxia or worsening respiratory symptoms. | |
| A 1 mg acetate dose and 0.85 mg Terlivaz dose are different amounts. | The prescribing information identifies 0.85 mg terlipressin as equivalent to 1 mg terlipressin acetate in the Terlivaz vial. | The numbers use different base and salt expressions for the same vial. |
Bottom line
Main takeaway
Terlipressin can improve kidney function in some people with severe liver disease and hepatorenal syndrome. Serious breathing problems and reduced blood flow to organs are important risks.
CONFIRM measured a kidney-response benefit alongside more respiratory complications. The treatment question includes oxygenation, fluid status, ischemia and severity of liver disease.
The published analysis reported 63/199 versus 17/101 after modifying its success definition and imputing some missing outcomes. The label reports 58/199 versus 16/101 and describes qualifying creatinine readings while on treatment. Both analyses describe the same randomized trial, but the exact reasons for all count differences are not established here.
Identity
What it is
Terlipressin is a 12-amino-acid synthetic vasopressin analog. It has its own receptor activity and is also metabolized to lysine-vasopressin.
Hepatorenal syndrome can develop in advanced liver disease when kidney function declines rapidly. The US Terlivaz indication is to improve kidney function in adults with this syndrome and a rapid reduction in kidney function.
Terlipressin is thought to improve kidney blood flow by changing circulation in the abdominal organs and increasing effective arterial blood volume and pressure. This vascular effect can also contribute to ischemic complications.
Use context
Routes, doses, and cycle patterns
The Terlivaz label specifies slow intravenous boluses, creatinine-based adjustment and oxygen monitoring. Concomitant albumin was strongly recommended in both trial groups.
Human studies and product labels
Terlivaz US label
- Purpose
- Improve kidney function in adults with rapidly progressive HRS
- Context
- US prescribing information
- Route
- Slow intravenous bolus over 2 minutes
- Amount
- 0.85 mg terlipressin, equivalent to 1 mg terlipressin acetate
- Frequency
- Every 6 hours initially
- Duration
- First 3 days, then adjusted by creatinine response; maximum 14 days
On day 4, the label describes continuing or increasing the dose according to creatinine change, and stopping if creatinine is at or above baseline. Oxygen saturation is assessed before treatment and monitored during it.
CONFIRM trial
- Purpose
- Verified reversal of type 1 hepatorenal syndrome
- Context
- Randomized placebo-controlled study
- Route
- Intravenous bolus
- Amount
- 1 mg terlipressin acetate, equivalent to 0.85 mg terlipressin initially
- Frequency
- Every 6 hours with response-based adjustment
- Duration
- Up to 14 days
The label describes an albumin fluid challenge for all patients. Concomitant albumin was strongly recommended; the publication reports it in 165/199 terlipressin patients and 92/101 placebo patients.
What varies
- Oxygenation and volume status: the label calls for baseline oxygen assessment, continuous monitoring and avoidance of use with grade 3 acute-on-chronic liver failure. Volume overload also increases respiratory risk.
- Baseline kidney function: the label says patients with serum creatinine above 5 mg/dL are unlikely to benefit.
- Dose expression: 0.85 mg terlipressin and 1 mg terlipressin acetate describe the same amount in one Terlivaz vial.
Research
Research evidence
CONFIRM found more verified kidney-response reversals with terlipressin than placebo. The published trial and US label report different counts for that endpoint. Respiratory failure was more frequent with terlipressin, and the trial did not establish a survival advantage.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| CONFIRM, published trial analysis | 300 adults with cirrhosis and type 1 hepatorenal syndrome | Randomized double-blind placebo-controlled trial | Terlipressin or placebo; concomitant albumin strongly recommended | The publication reported verified reversal of 63/199 with terlipressin versus 17/101 with placebo, or 32% versus 17%, using multiple imputation for some missing outcomes. | The label's trial description lists baseline creatinine above 7 mg/dL, shock, sepsis and/or uncontrolled bacterial infection among exclusions. The publication describes an infection exclusion for sepsis or uncontrolled bacterial infection treated with antibiotics for less than 2 days. The label reports different reversal counts. The trial did not establish a survival benefit. | Randomized, kidney-function endpoint |
| Terlivaz prescribing information | Adults with HRS and rapid reduction in kidney function | US prescribing information and trial analysis | Intravenous terlipressin with creatinine and oxygen monitoring | The label reports verified reversal in 58 of 199 treated patients and 16 of 101 placebo patients, or 29.1% versus 15.8%. Serious or fatal respiratory failure occurred in 14% versus 5%. | Label and publication counts differ. The label cautions that patients with serum creatinine above 5 mg/dL are unlikely to benefit. | Label and randomized trial context |
Use context
Reported use context
CONFIRM tested intravenous terlipressin or placebo in adults with cirrhosis and rapidly progressive hepatorenal syndrome. Concomitant albumin was strongly recommended in both groups.
Study and label context
1 mg terlipressin acetate every 6 hours initially, equivalent to 0.85 mg terlipressin.
Treatment continued for up to 14 days with creatinine-based adjustment.Cautions
Safety and unknowns
- Terlivaz may cause serious or fatal respiratory failure. Volume overload and grade 3 acute-on-chronic liver failure increase risk, according to the boxed warning. The label advises avoiding use with grade 3 acute-on-chronic liver failure.
- The label contraindicates treatment during hypoxia or worsening respiratory symptoms. It calls for assessing oxygen saturation before treatment and not initiating in hypoxic patients, for example with oxygen saturation below 90%, until oxygenation improves. It calls for continuous monitoring and stopping treatment if saturation falls below 90%.
- Ongoing coronary, peripheral or mesenteric ischemia is a contraindication. The label advises avoiding use in patients with a history of severe cardiovascular conditions, cerebrovascular or ischemic disease, and stopping treatment for signs or symptoms suggestive of an ischemic adverse reaction.
- Terlipressin may cause fetal harm. The label also notes that adverse reactions can make a patient ineligible for liver transplantation.
Product quality
Product identity and quality
Terlivaz is a single-dose intravenous product. Each vial contains 0.85 mg terlipressin, equivalent to 1 mg terlipressin acetate.
Base and salt expression
The label's 0.85 mg terlipressin and 1 mg acetate quantities refer to the same vial.
Mechanism
How it is proposed to work
Terlipressin acts on vasopressin receptors and changes blood flow in the abdominal circulation. This is thought to improve effective arterial blood volume and kidney blood flow in hepatorenal syndrome.
Terlipressin has activity itself and is also a prodrug for lysine-vasopressin. Its vasoconstrictor effects help explain both its clinical rationale and its ischemia precautions.
Details
Technical details
Sources
References
- 1.
DailyMed. Terlivaz prescribing information
US label for hepatorenal syndrome, dose expressed as terlipressin base, boxed respiratory warning and ischemia precautions.
- 2.
New England Journal of Medicine. Terlipressin plus albumin for type 1 hepatorenal syndrome: CONFIRM
doi:10.1056/NEJMoa2008290 PMID:33657294 NCT02770716
Randomized trial publication reporting kidney-response analysis methods, albumin use, survival and respiratory-event outcomes.
- 3.
PubMed. CONFIRM trial abstract
doi:10.1056/NEJMoa2008290 PMID:33657294
PubMed abstract of the same trial; detailed endpoint methods and concomitant albumin counts are in the full publication.