Terlipressin

TERLIVAZ contains terlipressin, a vasopressin receptor agonist. Terlipressin is a 12-amino acid peptide with the chemical name N -[ N -( N -glycylglycyl)glycyl]-8-L-lysinevasopressin. The structure of terlipressin acetate is shown below: Molecular formula: C 52 H 74 N 16 O 15 S 2 ∙ (C 2 H 4 O 2 ) n ; (n=number of acetate molecules; theoretical n=2.8) Average molecular weight: 1227.38 (as free base) TERLIVAZ is supplied as a sterile, preservative-free, lyophilized, white-to off-white powder for intravenous administration. Each vial contains 0.85 mg terlipressin, equivalent to 1 mg terlipressin acetate, and 10.0 mg mannitol. Glacial acetic acid and/or sodium hydroxide may be added to adjust pH at the time of manufacture. Chemical Structure

TERLIVAZ is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function. TERLIVAZ is a vasopressin receptor agonist indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function. ( 1 ) Limitation of Use Patients with a serum creatinine >5 mg/dL are unlikely to experience benefit. ( 1 ) Limitation of Use Patients with a serum creatinine > 5 mg/dL are unlikely to experience benefit.

TERLIVAZ is supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials containing 0.85 mg of terlipressin. Each vial is supplied in a carton (NDC 43825-200-01). 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.

Prior to initial dosing, assess patients for ACLF Grade 3 and obtain patient baseline oxygenation level. Monitor patient oxygen saturation with pulse oximetry. ( 2.1 ) Recommended Dosage Regimen: ( 2.2 ) Days 1 to 3 administer TERLIVAZ 0.85 mg (1 vial) intravenously every 6 hours. Day 4: Assess serum creatinine (SCr) versus baseline. If SCr has decreased by at least 30% from baseline, continue TERLIVAZ 0.85 mg (1 vial) intravenously every 6 hours. If SCr has decreased by less than 30% from baseline, dose may be increased to TERLIVAZ 1.7 mg (2 vials) intravenously every 6 hours. If SCr is at or above baseline value, discontinue TERLIVAZ. Continue TERLIVAZ until 24 hours after two consecutive SCr ≤1.5 mg/dL values at least 2 hours apart or a maximum of 14 days. See full prescribing information for instructions on preparation and administration ( 2.3 ). Flush IV line after administration. 2.1 Important Considerations Prior to Initiating and During Therapy Obtain baseline oxygen saturation (SpO 2 ) 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. Figure 1 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.

TERLIVAZ is contraindicated in patients experiencing hypoxia or worsening respiratory symptoms. TERLIVAZ is contraindicated in patients with ongoing coronary, peripheral or mesenteric ischemia. TERLIVAZ is contraindicated: In patients experiencing hypoxia or worsening respiratory symptoms. ( 4 ) In patients with ongoing coronary, peripheral, or mesenteric ischemia. ( 4 )

Serious or Fatal Respiratory Failure : Monitor patients for changes in respiratory status using pulse oximetry and regular clinical assessments. Actively manage intravascular volume overload and adjust TERLIVAZ therapy as appropriate. ( 5.1 ) Ineligibility for Liver Transplant : TERLIVAZ-related adverse reactions may make a patient ineligible for liver transplantation, if listed. ( 5.2 ) Ischemic Events : TERLIVAZ is a vasoconstrictor and can cause ischemic events (cardiac, peripheral, or mesenteric) that may require dose interruption or discontinuation. ( 5.3 ) Embryo-Fetal Toxicity : TERLIVAZ may cause fetal harm when used during pregnancy. Advise females of reproductive potential of the potential hazard to the fetus. ( 5.4 , 8.1 ) 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) ] .

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) ] .

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.

Risk Summary Based on findings from the published literature and on its mechanism of action, TERLIVAZ may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . In small, published studies, administration of a single intravenous dose of terlipressin to pregnant women during the first trimester induced uterine contractions and endometrial ischemia. The limited published data are not sufficient to determine a drug-associated risk for major birth defects or miscarriage . If TERLIVAZ is used during pregnancy, the patient should be informed of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In published reproductive toxicity animal studies, administration of terlipressin to pregnant guinea pigs at doses lower than the maximum recommended human dose of 4 mg/day caused a marked decrease in blood flow to the uterus and placenta. In rabbits, terlipressin is both embryotoxic and teratogenic (increased resorptions, increased implantation loss, fetal anomalies and fetal deformities).

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

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.

The following adverse reactions are discussed elsewhere in the labeling: Serious or Fatal Respiratory Failure [see Warnings and Precautions (5.1) ] Ischemic Events [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-800-844-2830 and www.Mallinckrodt.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Table 1: Adverse Reactions Reported by ≥4 % of TERLIVAZ-Treated Patients Patients, n (%) TERLIVAZ (N=200) Placebo (N=99) Abdominal pain 39 (19.5) 6 (6.1) Nausea 32 (16.0) 10 (10.1) Respiratory failure 31 (15.5) 7 (7.1) Diarrhea 26 (13.0) 7 (7.1) Dyspnea 25 (12.5) 5 (5.1) Fluid overload 17 (8.5) 3 (3.0) Pleural effusion 11 (5.5) 0 (0.0) Sepsis 11 (5.5) 1 (1.0) Bradycardia 10 (5.0) 0 (0.0) Ischemia-related events Ischemia-related events include: skin discoloration, cyanosis, ischemia and intestinal ischemia. 9 (4.5) 0 (0.0) 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.

Manifestations of TERLIVAZ overdose are expected to be similar to the adverse reactions described with therapeutic doses. In case of overdose, initiate close monitoring of vital signs, electrolytes, and potential ischemic events and initiate appropriate symptomatic treatment.