Terlipressin

Uses and Administration

Terlipressin is an inactive prodrug that is slowly converted in the body to lypressin, and has the general physiological actions of vasopressin ( Refer to ). It is given as the acetate although doses may be expressed as the base; 1 mg of terlipressin acetate is equivalent to about 0.85 mg of terlipressin.

Terlipressin acetate is used to control bleeding oesophageal varices and is given by intravenous injection in doses of 1 to 2 mg, followed by 1 to 2 mg every 4 to 6 hours if necessary, until bleeding is controlled, for up to 72 hours.

In the treatment of hepatorenal syndrome type 1 (see Refer to ) the recommended starting dose is the equivalent of 0.85 mg of terlipressin every 6 hours by slow intravenous bolus injection. If, after 3 days, serum creatinine has not decreased by at least 30% from its baseline value, the dose can be increased to 1.7 mg every 6 hours; however, such increases are not advised in patients with severe pre-existing cardiovascular disease or an ongoing significant adverse effect such as pulmonary oedema or ischaemia. Treatment should be continued until about 2 days after the patient achieves a reversal of hepatorenal syndrome, as indicated by a serum creatinine concentration of ≤ 132.6 micromoles/litre. The initial course of treatment may be continued for up to 2 weeks.

Terlipressin is under investigation in the treatment of shock.

(last reviewed 2012-10-18; last modified 2012-11-07)

Hepatorenal syndrome

Terlipressin given intravenously is used in the treatment of hepatorenal syndrome, a form of renal impairment associated with cirrhosis of the liver. A literature review1 of clinical studies and meta-analyses found evidence to suggest that renal function was improved in patients with hepatorenal syndrome when treated with terlipressin; a reduction in mortality was also shown in some but not all studies. However, relapse was noted in one study after terlipressin was stopped and adverse effects have occurred. In particular, systemic ischaemic effects can be a problem even in patients without a known risk of cardiovascular disease. The authors considered that terlipressin was a reasonable option for improving renal function before liver transplantation; however, definitive recommendations could not be given.

(last reviewed 2012-10-18; last modified 2012-11-07)

References

1. Mazur JE, et al.. Terlipressin in hepatorenal syndrome.Ann Pharmacother. 2011; 45: 380–7. PubMed

Shock

Terlipressin has vasopressor effects and has been tried1,2 in the management of septic shock ( Refer to ). In a group of 8 patients who could not be adequately managed with conventional vasopressor therapy, an intravenous bolus of terlipressin 1 to 2 mg produced a progressive increase in mean arterial pressure over 10 to 20 minutes that was sustained for at least 5 hours, allowing reduction or cessation of noradrenaline.3Similar beneficial results have also been reported by others.4,5The use of a continuous infusion of terlipressin (500 micrograms/hour for 6 hours followed by half this dose for a further 12 hours) has been described in one case and appeared to be effective.6There are also reports7,8 of a total of 20 children treated with bolus doses of 20 micrograms/kg every 4 hours for up to 72 hours. Terlipressin has also been used with some success as rescue therapy in doses of 7 to 20 micrograms/kg in children with extremely low cardiac output following open-heart surgery.9

(last reviewed 2012-10-18; last modified 2011-01-05)

References

1. Delmas A, et al.. Clinical review: vasopressin and terlipressin in septic shock patients.Crit Care. 2005; 9: 212–22. PubMed

2. Pesaturo AB, et al.. Terlipressin: vasopressin analog and novel drug for septic shock.Ann Pharmacother. 2006; 40: 2170–7. PubMed

3. O'Brien A, et al.. Terlipressin for norepinephrine-resistant septic shock.Lancet. 2002; 359: 1209–10. PubMed

4. Morelli A, et al.. Effects of terlipressin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock.Intensive Care Med. 2004; 30: 597–604. PubMed

5. Leone M, et al.. Terlipressin in catecholamine-resistant septic shock patients.Shock. 2004; 22: 314–19. PubMed

6. Jolley DH, et al.. Terlipressin infusion in catecholamine-resistant shock.Anaesth Intensive Care. 2003; 31: 560–4. PubMed

7. Rodríguez-Núñez A, et al.. Terlipressin for catecholamine-resistant septic shock in children.Intensive Care Med. 2004; 30: 477–80. PubMed

8. Rodríguez-Núñez A, et al.. Rescue treatment with terlipressin in children with refractory septic shock: a clinical study.Crit Care. 2006; 10: 20. PubMed online

9. Matok I, et al.. Terlipressin for children with extremely low cardiac output after open heart surgery.Ann Pharmacother. 2009; 43: 423–9. PubMed

Variceal haemorrhage

Systematic review has indicated1 that terlipressin is effective in the management of acute oesophageal variceal haemorrhage (see under Monoethanolamine, Refer to ), and reduces the relative risk of mortality by about one-third. Differences in efficacy from other therapies could not be conclusively shown. Comparison of a regimen of terlipressin given by intravenous bolus injection, plus glyceryl trinitrate given sublingually, with balloon tamponade in variceal bleeding has suggested similar efficacy.2 However, tamponade was successful in all patients that were previously unresponsive to terlipressin plus glyceryl trinitrate whereas this drug combination failed in all patients previously unresponsive to tamponade. A comparison of terlipressin and endoscopic injection sclerotherapy found them to be equally effective for the control of acute variceal bleeding.3

(last reviewed 2012-10-18; last modified 2010-08-19)

References

1. Ioannou GN, et al.. Terlipressin for acute esophageal variceal hemorrhage. Available in The Cochrane Database of Systematic Reviews; Issue 1. Chichester: John Wiley; 2003 (accessed 16/09/05). PubMed

2. Fort E, et al.. A randomized trial of terlipressin plus nitroglycerin vs balloon tamponade in the control of acute variceal hemorrhage.Hepatology. 1990; 11: 678–81. PubMed

3. Escorsell À, et al.. Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study.Hepatology. 2000; 32: 471–6. PubMed

Adverse Effects, Treatment and Precautions

As for Vasopressin, Refer to .

The pressor and antidiuretic effects of terlipressin are reported to be less marked than those of vasopressin.

(last reviewed 2012-10-18; last modified 2008-08-15)

Effects on electrolytes

A report of hypokalaemia in a patient receiving terlipressin.1

(last reviewed 2012-10-18; last modified 2004-03-24)

References

1. Stéphan F, Paillard F. Terlipressin-exacerbated hypokalaemia.Lancet. 1998; 351: 1249–50. PubMed

Effects on the skin

Ischaemic skin necrosis developed in 3 patients several days after starting terlipressin treatment.1 Skin lesions developed on the abdomen and lower limbs, which are not typical areas for ischaemia related to vasoconstrictors, and the authors concluded that obesity and venous insufficiency in these patients put them at particular risk.

(last reviewed 2012-10-18; last modified 2008-08-15)

References

1. Donnellan F, et al.. Ischaemic complications of Glypressin in liver disease: a case series.Br J Clin Pharmacol. 2007; 64: 550–2. PubMed

Interactions

As for Vasopressin, Refer to .

(last reviewed 2012-10-18; last modified 2012-11-07)

Pharmacokinetics

Following intravenous injection, terlipressin shows a biphasic decline in plasma concentrations, with distribution and elimination half-lives of between about 8 to 12 minutes and 50 to 80 minutes, respectively. Terlipressin is metabolised by tissue peptidases resulting in the slow release of lypressin; maximum plasma concentrations are reached after about 2 hours. Terlipressin is almost completely metabolised in the kidneys and liver, with less than 1% of terlipressin and less than 0.1% of lypressin excreted in the urine.

(last reviewed 2012-10-18; last modified 2012-11-01)

Preparations: Single-Ingredient

The following preparations list represents a compilation of all available salt forms or related substances for this drug product.

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

ARGENTINA: Glypressin¤;AUSTRALIA: Glypressin; Lucassin;AUSTRIA: Glycylpressin; Haemopressin;BELGIUM: Glypressin; Variquel¤;BRAZIL: Glypressin;CHINA: Glypressin (可利新); Remestyp (安立亭);CZECH REPUBLIC: Glypressin; Remestyp;DENMARK: Glypressin; Glypressine¤; Variquel;FINLAND: Glypressin; Stemflova;FRANCE: Glypressine; Haemopressin;GERMANY: Glycylpressin; Haemopressin;GREECE: Glypressin;HONG KONG: Glypressin;HUNGARY: Glypressin;IRELAND: Glypressin; Haemopressin; Variquel¤;ISRAEL: Glypressin;ITALY: Glipressina; Stemflova;MALAYSIA: Glypressin;MEXICO: Glyverase;NETHERLANDS: Glypressin; Haemopressin; Variquel;NORWAY: Glypressin; Stemflova¤;NEW ZEALAND: Glypressin;PHILIPPINES: Glypressin;POLAND: Glypressin; Remestyp;PORTUGAL: Glypressine; Variquel;RUSSIAN FEDERATION: Remestyp (Реместип);SINGAPORE: Glypressin;SPAIN: Glypressin; Variquel;SWEDEN: Glypressin; Variquel;SWITZERLAND: Glypressin; Haemopressin;THAILAND: Glypressin;TURKEY: Glypressin;UNITED KINGDOM: Glypressin; Variquel;UKRAINE: Glypressin (Глипрессин); Remestip (Реместип);

Last Updated 1/21/20

Package leaflet: Information for the user

GLYPRESSIN 1 mg/ 8.5 ml

Solution for Injection

Terlipressin acetate

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you

• Keep this leaflet. You may need to read it again.

• If you have any further questions, ask your doctor or nurse.

• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet:

1. What GLYPRESSIN is and what it is used for

2. What you need to know before you are given GLYPRESSIN

3. How you will be given GLYPRESSIN

4. Possible side effects

5. How to store GLYPRESSIN

6. Contents of the pack and other information

1. What GLYPRESSIN is and what it is used for

GLYPRESSIN solution for injection contains the active component terlipressin acetate. This medicinal

product also contains 1.33 mmols of sodium per 1 mg of terlipressin acetate, therefore please tell your

doctor if you are on a controlled sodium diet.

GLYPRESSIN is used in the treatment of bleeding oesophageal varices.

Oesophageal varices are enlarged blood vessels that form in the oesophagus (gullet) as a complication of

liver disease. They may burst and bleed which is a serious and life-threatening condition.

When injected into the bloodstream the active component, terlipressin acetate, is broken down to release

a substance called lysine vasopressin. This acts on the walls of the blood vessels, causing them to

narrow and restrict blood flow so that bleeding is reduced.

GLYPRESSIN is also used as an emergency treatment of type 1 hepatorenal syndrome in patients

with liver cirrhosis and ascites.

2. What you need to know before you are given GLYPRESSIN

Do not use GLYPRESSIN

- if you are allergic to terlipressin acetate or any of the other ingredients of this medicine (listed in section 6)

- if you are pregnant

Take special care with GLYPRESSIN

- if you have high blood pressure

- if you have heart disease

- if you have renal dysfunction

- if you have septic shock. Septic shock is a serious condition that occurs when a major infection leads

to low blood pressure and low blood flow.

- if you have atherosclerosis (a disease of the arteries in which fatty plaques develop on the inner lining

of the arteries, preventing blood from flowing normally)

- if you have asthma

- if you have respiratory failure

- in children and elderly patients as experience is limited in these age groups

Tell your doctor if any of these apply to you.

During treatment with GLYPRESSIN, your blood pressure, heart rate and fluid balance should be

monitored constantly.

Other medicines and GLYPRESSIN

Tell your doctor or other healthcare personnel if you are taking, have recently taken or might take any

other medicines. It is most important to tell your doctor if you are taking any kind of heart medication

(e.g. Propofol or beta-blockers) as their effect could be increased if used at the same time as GLYPRESSIN.

Pregnancy and breast-feeding

GLYPRESSIN should not be used during pregnancy.

GLYPRESSIN should not be used during breastfeeding as it is not known if GLYPRESSIN is transferred

into breast milk. Ask your doctor or other health care personnel for advice before taking any medicine.

Driving and using machines

Not applicable. GLYPRESSIN is a medicine that is only used in hospitals.

3. How you will be given GLYPRESSIN

GLYPRESSIN is a medicine that is used in hospitals and should only be given by qualified staff.

GLYPRESSIN is injected intravenously (directly into the bloodstream).

Short term management of bleeding oesophageal varices

The starting dose of GLYPRESSIN in sudden bleeding from oesophageal varices is 2 mg (2x8.5ml)

terlipressin acetate. Further doses are usually 1-2 mg terlipressin acetate every 4 hours until bleeding has

been controlled for 24 hours.

Treatment should last a maximum of 48 hours.

After the starting dose your dose may be adjusted according to your body weight or if you experience any

side effects.

Type I hepatorenal syndrome

The usual dose of GLYPRESSIN in Type 1 hepatorenal syndrome is 3 to 4 mg terlipressin acetate every

24 hours as 3 or 4 administrations. In the absence of any reduction of serum creatinine after 3 days

of treatment your doctor should stop your treatment with GLYPRESSIN. When a reduction in serum

creatinine is seen treatment with GLYPRESSIN should be continued with the standard average duration of

treatment being 10 days.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Commonly reported side effects (affect between 1 and 10 of every 100 patients treated):

- Headache

- Bradycardia (very slow heart rate)

- Increased blood pressure

- Peripheral constriction of blood vessels (inadequate blood flow to the tissue) resulting in paleness

- Transient stomach pain

- Transient diarrhoea

Uncommonly reported side effects (affect between 1 and 10 of every 1,000 patients treated):

- Low blood sodium if fluid not monitored

- Irregular heart beat

- Increased pulse rate

- Chest pain

- Myocardial infarction (heart attack)

- Pulmonary oedema

- Torsade de pointes (acute cardiac event)

- Heart failure. Symptoms include shortness of breath, tiredness and swollen ankles

- Inadequate blood flow to the guts

- Peripheral cyanosis (bluish discolouration of the skin caused by lack of oxygen)

- Hot flushes

- Respiratory distress and respiratory failure (difficulties in breathing)

- Transient nausea

- Transient vomiting

- Skin necrosis (tissue damage)

- Uterine constriction (constriction of the womb)

- Decreased uterine blood flow

- Injection site necrosis (tissue damage)

Rarely reported side effects (affect between 1 and 10 of every 10,000 patients treated):

- Dyspnoea (difficulties in breathing)

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance,

Earlsfort Terrace, IRL – Dublin 2. Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie;

E-mail: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store GLYPRESSIN

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP.

The expiry date refers to the last day of that month.

Store in a refrigerator (2-8°C). Keep the ampoules in the outer carton in order to protect from light.

Each ampoule is for single use only. Discard any unused solution.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What GLYPRESSIN contains

8.5 ml of injection solution contains 1 mg of terlipressin acetate equivalent to 0.12 mg terlipressin acetate/ml.

The other ingredients are: sodium chloride, acetic acid, sodium acetate, water for injection.

What GLYPRESSIN looks like and contents of the pack

The product is a clear, colourless solution for injection.

GLYPRESSIN is available in one pack size:

5 ampoules with 8.5 ml solution each

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Ferring Ireland Ltd., United Drug House, Magna Drive, Magna Business Park, Citywest Road, Dublin 24

PA 1009/4/2

Manufacturer:

Ferring-Léčiva a.s., K Rybníku 475, 252 42 Jesenice near Prague, Czech Republic

This leaflet was last revised in 11/2018.

GLYPRESSIN, FERRING and the FERRING Logo are trademarks of Ferring B.V. © 2015 Ferring B.V