Limitation of Use

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

2.1 Important Considerations Prior to Initiating and During Therapy

Obtain baseline oxygen saturation (SpO2) prior to administering the first dose of TERLIVAZ. During treatment, monitor patient oxygen saturation using continuous pulse oximetry. Do not use TERLIVAZ treatment in patients experiencing hypoxia until hypoxia resolves [see Contraindications (4), and Warnings and Precautions (5.1)].

Assess Acute-on-Chronic Liver Failure (ACLF) Grade and volume status before initiating TERLIVAZ [see Warnings and Precautions (5.1) and References (15)].

2.2 Recommended Dosage

Record last available serum creatinine (SCr) value prior to initiating treatment (baseline SCr). The recommended starting dosage is TERLIVAZ 0.85 mg every 6 hours by slow intravenous bolus injection (over 2 minutes) on Days 1 through 3. Adjust the dose on Day 4 based on changes from baseline SCr using the dosing chart (Figure 1).

Figure 1: Dosing Chart

a Baseline SCr is the last available serum creatinine before initiating treatment.

2.3 Preparation and Administration

Reconstitute each vial with 5 mL of 0.9% Sodium Chloride Injection to prepare a 0.85 mg/5 mL solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Administer TERLIVAZ through a peripheral or central line. A dedicated central line is not required. Flush the line after TERLIVAZ administration.

If not administered immediately, store TERLIVAZ at 2°C to 8°C (36°F to 46°F) for up to 48 hours. Do not freeze. The reconstituted solution does not need protection from light.

5.1 Serious or Fatal Respiratory Failure

In the primary clinical trial [see Clinical Studies (14)], serious or fatal respiratory failure occurred in 14% of patients treated with TERLIVAZ compared to 5% of patients on placebo.

Obtain baseline oxygen saturation and do not initiate TERLIVAZ in hypoxic patients [see Contraindications (4)]. 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.

Patients with fluid overload may be at increased risk of respiratory failure. Manage intravascular volume overload by reducing or discontinuing the administration of albumin and/or other fluids and judicious use of diuretics. Temporarily interrupt, reduce, or discontinue TERLIVAZ treatment until patient volume status improves [see Dosage and Administration (2.1)].

Avoid use in patients with ACLF Grade 3 because they are at significant risk for respiratory failure [see References (15)].

5.2 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 [see Adverse Reactions (6.1)].

5.3 Ischemic Events

TERLIVAZ may cause cardiac, cerebrovascular, peripheral, or mesenteric ischemia. Avoid use of TERLIVAZ in patients with a history of severe cardiovascular conditions, cerebrovascular and ischemic disease. Discontinue TERLIVAZ in patients who experience signs or symptoms suggestive of ischemic adverse reactions [see Dosage and Administration (2.1) and Adverse Reactions (6.1)].

5.4 Embryo-Fetal Toxicity

TERLIVAZ may cause fetal harm when administered to a pregnant woman based on the mechanism of action and data from published literature. Terlipressin induces uterine contractions and endometrial ischemia in both humans and animals. If this drug is used during pregnancy, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of TERLIVAZ cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of TERLIVAZ was evaluated in the CONFIRM trial [see Clinical Studies (14)]. The average daily dose of TERLIVAZ was 3.1 mg (range 0.8 to 5.8 mg), with a mean duration of exposure to TERLIVAZ of 6.2 days (range 1 to 15 days).

Treatment discontinuation due to adverse events occurred in 12.0% (24/200) of patients receiving TERLIVAZ and 5.1% (5/99) of patients receiving placebo. The most common adverse reactions that led to TERLIVAZ discontinuation were respiratory failure, abdominal pain, and intestinal ischemia/obstruction.

Table 1 lists adverse reactions that occurred more commonly on TERLIVAZ than on placebo, and in at least 4% of patients treated with TERLIVAZ in the CONFIRM trial. The most commonly observed adverse reactions in TERLIVAZ-treated patients (≥10%) were abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea.

6.2 Postmarketing Experience

Adverse reactions reported from the worldwide postmarketing experience with terlipressin include headache, hyponatremia, skin necrosis and gangrene. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to terlipressin exposure.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of TERLIVAZ have not been established in pediatric patients.

8.5 Geriatric Use

Of the total number of patients in clinical studies treated with TERLIVAZ, 55 (16%) were ≥65 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Terlipressin is a synthetic vasopressin analogue with twice the selectivity for vasopressin V1 receptors versus V2 receptors. Terlipressin acts as both a prodrug for lysine-vasopressin, as well as having pharmacologic activity on its own. Terlipressin is thought to increase renal blood flow in patients with hepatorenal syndrome by reducing portal hypertension and blood circulation in portal vessels and increasing effective arterial volume and mean arterial pressure (MAP).

12.2 Pharmacodynamics

After administration of a single 0.85 mg dose of terlipressin in patients with hepatorenal syndrome type 1 (HRS-1), an increase in the diastolic, systolic, and mean arterial pressure (MAP), and decrease in heart rate were evident within 5 minutes after dosing and were maintained for at least 6 hours after dosing. The maximum change in blood pressure and heart rate occurred at 1.2 to 2 hours post dose. For MAP, the estimated maximum effect was an increase of 16.2 mmHg. The estimated maximum effect for heart rate was a decrease of 10.6 beats/minute.

12.3 Pharmacokinetics

The pharmacokinetic parameters of terlipressin and its major active metabolite, lysine-vasopressin, were derived from population pharmacokinetic modeling with sparse PK samples from 69 patients with HRS-1.

Following a 1 mg IV injection of terlipressin acetate, the median Cmax, AUC24h and Cave of terlipressin at steady state was 70.5 ng/mL, 123 ng×hr/mL and 14.2 ng/mL, respectively. The median Cmax, AUC24h and Cave of lysine-vasopressin were 1.2 ng/mL, 11.2 ng×hr/mL and 0.5 ng/mL, respectively.

Terlipressin and lysine-vasopressin exhibit linear pharmacokinetics in healthy subjects. Plasma concentrations of terlipressin demonstrate proportional increases with the dose administered.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with terlipressin.

Terlipressin was not mutagenic or clastogenic in the following tests: in vitro bacterial reverse mutation assay, in vivo mouse micronucleus assay, and in vitro mammalian cell (CHO) chromosome aberration assay.

No studies with terlipressin have been conducted in animals to evaluate its effect on fertility.

Store TERLIVAZ vials in the carton under refrigerated conditions at 2°C to 8°C (36°F to 46°F). Store in the original carton to protect from light prior to reconstitution.

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that TERLIVAZ may cause fetal harm and to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].