BRIEF SUMMARY-

TERLIPRESSIN- (Sep 2022)

Indn-  To improve kidney function with hepatorenal synderome     

Comp- For injection: g (1 vial) as a lyophilized powder in a single-dose vial for reconstitution.  Recommended Dosage Regimen:Day 4: Assess serum creatinine (SCr) versus baseline

ADR-  The most common adverse reactions (=10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea.

CI-  is contraindicated: In patients experiencing hypoxia or worsening respiratory symptoms.  In patients with ongoing coronary, peripheral, or mesenteric ischemia.

 WARNINGS-

• 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  therapy as appropriate.

Pat inform-

Embryo-Fetal Toxicity -   Inform female patients of reproductive potential that the drug may cause fetal harm and to inform their prescriber of a known or suspected pregnancy

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U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 22

Name-                        TERLIVAZ

Active Ingredient -   Terlipressin

Pharmacological Classification- To improve kidney function with hepatorenal                                                                  synderome                                                                  

Date of Approval-         9/14/2022                                                                                                                    

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                             TERLIVAZ® safely and effectively.                                                                               See full prescribing information for TERLIVAZ. TERLIVAZ (terlipressin) for injection, for intravenous use

Initial U.S. Approval: 2022

WARNING: SERIOUS OR FATAL RESPIRATORY FAILURE-                                TERLIVAZ may cause serious or fatal respiratory failure. Patients with volume overload or with 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% 

 INDICATIONS AND USAGE-                                                                                   TERLIVAZ is a vasopressin receptor agonist indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.

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

ADVERSE REACTIONS-

 The most common adverse reactions (=10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea.

CONTRAINDICATIONS-

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

 WARNINGS AND PRECAUTIONS-

 • 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.

 • Ineligibility for Liver Transplant: TERLIVAZ-related adverse reactions may make a patient ineligible for liver transplantation, if listed.

 • Ischemic Events: TERLIVAZ is a vasoconstrictor and can cause ischemic events (cardiac, peripheral, or mesenteric) that may require dose interruption or discontinuation.

 • Embryo-Fetal Toxicity: TERLIVAZ may cause fetal harm when used during pregnancy. Advise females of reproductive potential of the potential hazard to the fetus.

DOSAGE AND ADMINISTRATION                                                                                   • Prior to initial dosing, assess patients for ACLF Grade 3 and obtain patient baseline oxygenation level. Monitor patient oxygen saturation with pulse oximetry.

 • Recommended Dosage Regimen: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

 Flush IV line after administration.

DOSAGE FORMS AND STRENGTHS-

For injection: TERLIVAZ 0.85 mg (1 vial) as a lyophilized powder in a single-dose vial for reconstitution. 

PATIENT COUNSELING INFORMATION-

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 

. Distributed by: Mallinckrodt Hospital Products Inc. Bedminster, NJ 07921, USA Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. ©2022 Mallinckrodt. For a list of patents, see https://www.mallinckrodt.com/patents/ Part # PCR-750-16379

CLINICAL PHARMACOLOGY-

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). 

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.

Cardiac Electrophysiology-                                                                                         The effect of terlipressin on QTc interval was evaluated in 41 patients with HRS-1. Patients received an initial dose of 1 mg terlipressin acetate every 6 hours for a period of up to 14 days.

No clinically meaningful changes from baseline were detected in the trial based on the Fridericia correction method. Increases of the mean QTc interval of <10 ms were reported.

3. Pharmacokinetics-                                                                                                   The pharmacokinetic parameters of terlipressin and its major active metabolite, lysinevasopressin, 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.

Distribution-                                                                                                                  The volume of distribution (Vd) of terlipressin was 6.3 L and 1370 L for lysine-vasopressin.

Elimination-                                                                                                                   The clearance of terlipressin was 27.4 L/hr and 318 L/hr for lysine-vasopressin. There were no dose-dependent changes in the elimination rate constant of terlipressin in healthy subjects.

Clearance of terlipressin in HRS-1 patients increased with body weight, while body weight had no effect on the clearance of lysine-vasopressin.

The terminal half-life of terlipressin was 0.9 hours and 3.0 hours for lysine-vasopressin.

Metabolism-                                                                                                               Terlipressin is metabolized by cleavage of the N-terminal glycyl residues of terlipressin by various tissue peptidases, resulting in release of the pharmacologically active metabolite lysinevasopressin.

Once formed, lysine-vasopressin is metabolized by body tissue via various peptidase-mediated routes. Terlipressin is not metabolized in blood or plasma.

Due to the ubiquitous nature of peptidases in body tissue, it is unlikely that the metabolism of terlipressin will be affected by disease state or other drugs.

Excretion-                                                                                                                       Less than 1% of terlipressin and <0.1% of lysine-vasopressin is excreted in urine in healthy subjects.

Specific Populations-                                                                                                     Gender, age, creatinine clearance, Child-Pugh score, serum alkaline phosphatase, serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and total bilirubin do not appear to have any clinically significant effect on clearance of either terlipressin or lysinevasopressin.

Drug Interactions-                                                                                                           In vitro studies in human liver microsomes demonstrated that there was little or no evidence that terlipressin was a direct-, time-, or metabolism-dependent inhibitor and inducer of any of the CYP enzymes evaluated. In addition, there was little or no evidence that terlipressin is an inhibitor and substrate of human ABC and SLC transporters.

No significant drug-drug interactions are anticipated with TERLIVAZ.

USE IN SPECIFIC POPULATIONS

1. Pregnancy 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

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.

2. Lactation Risk Summary-                                                                                     There are no data on the presence of terlipressin in human or animal milk, the effects on the breastfed infant, or the effect on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TERLIVAZ and any potential adverse effects on the breastfed child from TERLIVAZ or from the underlying maternal condition.

3.Pediatric Use-                                                                                                        Safety and effectiveness of TERLIVAZ have not been established in pediatric patients.

4. 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.

5. Hepatic Impairment-                                                                                                  No dose adjustment is required in patients with hepatic impairment

OVERDOSAGE-                                                                                                       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.