Australian public assessment report for Terlipressin

Attachment 1. Product Information

The Product Information approved at the time this AusPAR was published is at Attachment 1. For the most recent Product Information please refer to the TGA website at .

Attachment 2. Extract from the Clinical Evaluation Report

1^ The drug will be referred to as simply terlipressin for the remainder of this AusPAR.

2^ The shelf life of this product has since been extended to 36 months at 28°C, protected from light (approved by the TGA on 20 June 2013).

3^ Estimated from data in Study CB06-5013-R-TX where a C_{5 min} of 352 ng/mL was seen with a 150 μg/kg dose.

4^ Manning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G. Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V_1a, V_1b, V₂ and OT receptors: research tools and potential therapeutic agents. Prog Brain Res 2008; 170: Chapter 37.

5^ EMEA, Committee for Medicinal Products for Human Use (CHMP), 17 March 2005. Guideline on the Evaluation of Control Samples in Nonclinical Safety Studies: Checking for Contamination with the Test Substance, CPMP/SWP/1094/04.

6^ Forsling ML, Aziz LA, Miller M, Davies R, Donovan B. Conversion of triglycylvasopressin to lysine-vasopressin in man. J Endocr 1980; 85: 237-244.

7^ pp. 3 - 8 of the Rules Governing Medicinal Products in the European Union - EudraLex - Medicinal products for human use, 1998 Edition: Volume 3B - Safety and the Environment - 3BS1a. Single Dose Toxicity.

8^ EMEA, ICH Topic S9, Nonclinical Evaluation for Anticancer Pharmaceuticals, November 2009. Note for Guidance on Nonclinical Evaluation for Anticancer Pharmaceuticals (EMEA/CHMP/ICH/646107/2008).

9^ EMEA, Committee for Proprietary Medicinal Products (CPMP), May 1999. ICH Topic S4. Note for Guidance on Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing), CPMP/ICH/300/95.

10^ ICH Topic M3 (R2), Note For Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals (CPMP/ICH/286/95).

11^ Meidan R, Hsueh AJW. Identification and characterisation of arginine vasopressin receptors in the rat testis. Endocrin 1985; 116: 416-423.

12^ Hinko A, Soloff MS. Characterisation of oxytocin receptors in rabbit amnion involved in the production of prostaglandin E2. Endocrin 1992; 130: 3547-3553.

13^ Fuchs, A-R, Dawood, YM. Oxytocin release and uterine activation during parturition in rabbits. Endocrin 1981; 107: 1117-1126.

14^ Love AM, Vickers TH. Vasopressin induced dysmelia in rats and its relation to amniocentesis dysmelia. Br J Exp Path 1973; 54: 291-297.

15^ Chernoff N, Grabowski CT. Responses of the rat foetus to maternal injections of adrenaline and vasopressin. Br J Pharmacol 1971; 43: 270-278.

16^ Laudanski T, Akerlund M. Uterine effects of N-alpha-triglycyl-(8-lysine)-vasopressin and 8-lysine-vasopressin in the first trimester of pregnancy. Contraception 1980; 22: 199-208.

17^ Qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified.

18^ Plate R. Studies on the localization and kinetics in the degradation of the synthetic vasopressin slow-release preparation. Triglycyl-lysine-vasopressin. Analytical methods and pharmacological experiments. Hanover, Germany: Hanover School of Medicine; 1995.

19^ Forsling ML, Aziz LA, Miller M, Davis R, Donovan B. Conversion of triglycylvasopressin to lysine-vasopressin in man. J Endocr. 1980; 85:237-244.

20^ Nilsson G, Lindbom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after single IV. doses to healthy volunteers. Drugs Exptl Clin Res. 1990; 16:307-314.

21^ Arroyo V, Jiménez W. Complications of cirrhosis. II. Renal and circulatory dysfunction. Lights and shadows in an important clinical problem. J Hepatol 2000; 32: 157-170.

22^ Kiszka-Kanowitz M, Henriksen JH, Hansen EF, Møller S, Bendtsen F. Effect of terlipressin on blood volume distribution in patients with cirrhosis. Scand J Gastroenterol 2004; 39: 486-492.

23^ Gines P, Guevara M, Arroyo V, Rodes J. Hepatorenal Syndrome. Lancet 2003; 362: 1819-1827.

24^ p = 0.055, Report section 7.4 page 332.

25^ P = 0.061, Table 4.3.49; Clinical study report

26^ Bataller R, Gines P, Arroyo V. Hepatorenal Syndrome. Semin Liv Dis 1997; 17:233-247.

27^ Rimola A, Gavaler JS, Schade RR, el-Lankany S, Starzl TE, Van Thiel DH. Effects of renal impairment on liver transplantation. Gastroentology 1987; 93: 148-156.

28^ Rimola found that Univariate analysis indicated that 7 of the 16 selected variables had prognostic significance for predicting mortality: the preoperative existence of renal impairment or of encephalopathy. The preoperative serum bilirubin (>16 mg/dl) and albumin levels. The postoperative occurrence of late renal impairment, liver graft failure and the occurrence of a serious postoperative infection. Analysing these variables only a serious postoperative infection (p < 0.001), livergraft failure (p < 0.001), and preoperative renal dysfunction (p < 0.01) were found to be independent indicators of a fatal outcome.

29^ Primary objective: to investigate the effects of treatment with terlipressin and albumin on the survival of patients with hepatic cirrhosis and HRS Type 1 or 2.

To evaluate whether the improvement in renal function, in the event this occurs, results in an increase in the probability of survival to transplantation and in a reduction of post-transplant complications.

30^ QT interval: a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A prolonged QT interval is a risk factor for ventricular tachyarrhythmias and sudden death. The QT interval is dependent on the heart rate (the faster the heart rate, the shorter the QT interval). To correct for changes in heart rate and thereby improve the detection of patients at increased risk of ventricular arrhythmia, a heart rate-corrected QT interval QTc is often calculated.

31^ Yang YZ, Dan ZL, Liu NZ. Efficacy of terlipressin in treatment of liver cirrhosis with hepatorenal syndrome. J Intern Med 2001.

32^ Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A. Octreotide in hepatorenal syndrome: A randomized, double-blind, placebo-controlled, crossover study. Hepatology 2003; 38: 238-243.

33^ Rimola 1987. Rimola A, Gavaler JS, Schade RR, el-Lankany S, Starzl TE, Van Thiel DH. Effects of renal impairment on liver transplantation. Gastroentology 1987; 93: 148-156.

34^ Routine pharmacovigilance practices involve the following activities:

All suspected adverse reactions that are reported to the personnel of the company are collected and collated in an accessible manner;

Reporting to regulatory authorities;

Continuous monitoring of the safety profiles of approved products including signal detection and updating of labeling;

Submission of PSURs;

Meeting other local regulatory agency requirements.

35^ Routine risk minimisation activities may be limited to ensuring that suitable warnings are included in the product information or by careful use of labelling and packaging.

36^ Gonwa 1995: Impact of pretransplant renal function on survival after liver transplantation.