ADVERSE REACTIONS

Adverse reactions in the CONFIRM trial

Most Common Adverse Reactions (Reported by ≥4% of patients treated with TERLIVAZ®)¹
	Patients, n (%)		Patients, n (%)
	TERLIVAZ + Albumin (n=200)	Placebo + Albumin (n=99)
Gastrointestinal events
Abdominal pain	39 (19.5)	6 (6.1)
Nausea	32 (16.0)	10 (10.1)
Diarrhea	26 (13.0)	7 (7.1)
Respiratory events
Respiratory failure	31 (15.5)	7 (7.1)
Patients intubated, n/total (%)^2,a	20/31 (64.5)	5/7 (71.4)
Dyspnea	25 (12.5)	5 (5.1)
Fluid overload	17 (8.5)	3 (3.0)
Pleural effusion	11 (5.5)	0.0
Infections
Sepsis	11 (5.5)	1 (1.0)
Cardiovascular events
Bradycardia	10 (5.0)	0.0
Ischemia-related events^b	9 (4.5)	0.0

^aNot all patients who experienced severe respiratory failure were intubated.

^bIschemia-related events include preferred terms: skin discoloration, cyanosis, ischemia, and intestinal ischemia.

In the CONFIRM trial, respiratory failure was newly identified as a serious adverse event. It has been proposed that both albumin and TERLIVAZ played a role in the development of pulmonary edema leading to respiratory failure in certain patients. The highest rate of respiratory failure was observed in patients who received both TERLIVAZ and high-dose albumin.¹

Patients experiencing hypoxia defined as SpO₂ <90% or multi-organ failure categorized as acute-on-chronic liver failure (ACLF) Grade 3 were at higher risk for respiratory failure. Appropriate patient selection and management are important considerations when treating with TERLIVAZ.¹

RISK MONITORING

Prior to and during treatment, monitor for risk of respiratory failure for all patients¹

During CONFIRM, when respiratory failure occurred with TERLIVAZ, it had a median onset of 5 days, an average onset of 7.5 days, and a range of 1 to 67 days.²

ACLF, acute-on-chronic liver failure.

UNDERSTANDING RESPIRATORY EVENTS

Proposed pathophysiology of respiratory failure in HRS patients

HRS, hepatorenal syndrome.

Respiratory failure may be the result of pulmonary edema^3-6 due to increases in:
- Cardiac preload that may result from high volumes of albumin^7,8
- Cardiac afterload that may result from increased vascular resistance due to use of terlipressin^9-11
Intravascular volume overload and pulmonary edema may be challenges for very ill cirrhotic patients (ie, acute-on-chronic liver failure Grade 3) and may be exacerbated by high doses of albumin, particularly when given with terlipressin^7,12-14

HRS, hepatorenal syndrome.

RESPIRATORY EVENTS BY ACLF IN THE CONFIRM TRIAL

Patients with ACLF Grade 3 were more likely to experience respiratory failure than patients with ACLF Grade 0-2²

ACLF Grade is an important consideration when determining if a patient is appropriate for terlipressin. ACLF Grade 3 occurs when 3 of the organs/systems listed in the right table are in failure as defined by the cutoff criteria.

ACLF, acute-on-chronic liver failure; CLIF-SOFA, chronic liver failure-sequential organ failure assessment; FiO₂, fraction of inspired oxygen; HE, hepatic encephalopathy; INR, international normalized ratio; PaO₂, partial pressure of oxygen in the blood; SCr, serum creatinine; SpO₂, oxygen saturation.

^aSerious respiratory failure events were reported as respiratory failure and/or acute respiratory failure by investigators.

^bBased on CLIF-SOFA scoring system.

RESPIRATORY EVENTS BY PRIOR ALBUMIN USE: POOLED DATA FROM 2 TRIALS, CONFIRM AND REVERSE

Respiratory failure rates were greater in patients who received larger amounts of albumin¹⁶

Respiratory Failure Rate by Prior Albumin Administered Graph

Consistent with the hypothesis that both albumin and terlipressin play roles in respiratory failure, patients receiving terlipressin and albumin experienced higher rates of respiratory failure than those receiving placebo and albumin. However, when patients received more than the recommended albumin challenge dose of ≤100 g per day for 48 hours, respiratory failure rates were higher. The highest rate of respiratory failure was observed in patients who received both TERLIVAZ and high-dose albumin.^13,16-18

SAE, serious adverse event.

Note: if a subject experienced an SAE during the retreatment period, it is combined with the initial period.

Pooled data from 2 clinical trials including pivotal trial.

^aRespiratory failure SAEs include acute respiratory failure and respiratory failure SAEs. No significant differences were seen in the rate of respiratory failure SAEs at all levels of prior albumin administration.

Appropriate treatment with TERLIVAZ begins with proper patient selection

LEARN ABOUT PATIENT SELECTION AND MANAGEMENT

INDICATION AND LIMITATION OF USE

TERLIVAZ is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.

Patients with a serum creatinine >5 mg/dL are unlikely to experience benefit.

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS OR FATAL RESPIRATORY FAILURE

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.
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%.

Contraindications

TERLIVAZ is contraindicated:

In patients experiencing hypoxia or worsening respiratory symptoms.
In patients with ongoing coronary, peripheral, or mesenteric ischemia.

Warnings and Precautions

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.
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.
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.
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.