Australian public assessment report for Terlipressin

I. Introduction to product submission

Submission details

Type of submission:	New Chemical Entity
Decision:	Approved
Date of decision:	9 January 2012

Active ingredient:	Terlipressin
Product name:	Lucassin
sponsor’s name and address:	Ikaria Australia Pty Ltd 695 Burke Road Hawthorn East Vic 3123
Dose form:	Powder for injection
Strength:	0.85 mg per vial
Container:	Type I glass vial fitted with grey bromobutyl rubber stopper and aluminium seal with green plastic flip-off cap.
Pack size(s):	1 or 12 vials per carton
Approved Therapeutic use:	The treatment of patients with hepatorenal syndrome (HRS) Type 1 who are actively being considered for a liver transplant.
Route of administration:	Intravenous (IV)
Dosage:	0.85 mg terlipressin (free base) every 6 h (starting dose).
ARTG Number:	176845

Product background

Hepatorenal syndrome (HRS) is a serious complication of advanced cirrhosis, characterised by renal failure and major disturbances in circulatory function. HRS is at the end of a spectrum of functional renal abnormalities caused by severe vasoconstriction of the renal circulation which leads to a pronounced reduction in glomerular filtration rate. The more common form of HRS is Type 1 (HRS-1), which is characterised by an abrupt onset and rapid progression of renal dysfunction defined by a doubling of the initial serum creatinine to a level greater than 220 µmol/L in less than 2 weeks. In contrast, Type 2 HRS has a more protracted course, characterised by a slower decline in renal function, often over months. Diagnosis of HRS includes decreased creatinine clearance or elevated serum creatinine and is made after exclusion of other disorders that can cause renal failure in cirrhosis.

It has been estimated that untreated HRS-1 carries a mortality of approximately 80% at 2 weeks, with only 10% of patients surviving more than 3 months.

The key pathophysiological change responsible for the development of HRS in cirrhotic patients with advanced liver dysfunction is the development of arterial vasodilatation. This occurs primarily within the splanchnic circulation and is mediated by the local release of potent vasodilators, of which the most important is nitric oxide. The resultant decrease in systemic vascular resistance and effective circulating blood volume precipitates a chain of sequelae including the reflex secretion of vasoconstrictor hormones such as renin, angiotensin, antidiuretic hormone, catecholamines and endothelin, as well as increased sympathetic nervous system activation. These latter changes lead to renal vasoconstriction, reduced renal perfusion, reduction in glomerular filtration rate and renal failure.

The definitive treatment for HRS-1 is liver transplantation, supported by pharmacotherapy either as bridging treatment to transplantation, or for the management of those patients who are not liver transplant candidates.

Therapeutic Guidelines Gastrointestinal notes that this condition occurs predominantly in patients with advanced cirrhosis and usually in the setting of severe ascites and hyponatraemia and may be precipitated by infection, diuretics, nephrotoxic drugs, gastrointestinal bleeding or large volume paracentesis. It recommends that particular care should be taken to avoid renal impairment in patients at risk for HRS and that initial management involve correction of hypovolaemia and other precipitants and, if renal dysfunction fails to improve, that consideration be given to the use of terlipressin 0.5 to 2 mg intravenously (IV) 6-12 hourly + human albumin 20% 100 mL IV twice daily (bd) both given for 7-14 days. The Guideline then recommends that patients who have had an episode of HRS be considered for liver transplantation.

Lucassin contains terlipressin, which is a systemic vasoconstrictor, via vasopressin V₁ receptors, acting both as a prodrug for lysine-vasopressin (LVP) and having pharmacological activity on its own, albeit of lower potency than LVP. The duration of action of terlipressin is longer than vasopressin and is due to cleavage of the N-terminal glycyl residues of terlipressin by various tissue peptidases, resulting in release of the pharmacologically active metabolite LVP.

An expert in the field was given access to the clinical evaluation report (CER) by the sponsor, and independently wrote to the TGA advising that in Australia terlipressin is used as a “bridge to transplant” in patients with HRS. Terlipressin is used in this setting to improve renal function before transplantation as it avoids dialysis and significant renal impairment. It is the current standard of care in patients with HRS. Terlipressin is available under the Special Access Scheme.

This AusPAR describes the evaluation of a submission by Ikaria Australia Pty Ltd (the sponsor) to register Lucassin for treatment of HRS-1.

Proposed dosage is 0.85 mg terlipressin (free base) every 6 hours by slow IV bolus injection. Dose may be increased to 1.7 mg every 6 hours if serum creatinine has not decreased by at least 30% from the baseline value after 3 days. Treatment should be continued until about 2 days after the patient achieves HRS reversal (serum creatinine ≤1.5 mg/dL [that is, ≤132.6 µmol/L]). The maximum duration of treatment is 2 weeks.

Regulatory status

Lucassin was designated by the TGA as an Orphan Drug on 25 June 2010 for the treatment of patients with hepatorenal syndrome Type 1 (HRS-1) and for the treatment of oesophageal variceal haemorrhage (OVH).

A similar application has been submitted in the US for the proposed indication of hepatorenal syndrome, Type 1 (HRS-1), as an orphan designated, fast tracked, rolling New Drug Application (NDA) commencing on 27 May 2008. The application is under consideration. There have been no other submissions.

Terlipressin was first approved in the early 1980s in Germany for treatment of patients with oesophageal variceal haemorrhage. Products containing terlipressin have been marketed in Europe, South America and Asia for treatment of oesophageal variceal haemorrhage. Terlipressin is also approved for the treatment of HRS in France, India, Ireland, Mexico, Portugal, South Korea, Taiwan and Spain.

Product Information

The approved Product Information (PI) current at the time this AusPAR was prepared can be found as Attachment 1.