Consumer medicine information

Glypressin

Terlipressin

BRAND INFORMATION

Brand name

Glypressin Solution

Active ingredient

Terlipressin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Glypressin.

What is in this leaflet

This leaflet answers some common questions about GLYPRESSIN.

It does not contain all of the available information. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given GLYPRESSIN against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What GLYPRESSIN is used for

GLYPRESSIN contains terlipressin.

GLYPRESSIN is used to treat Bleeding Oesophageal Varices (BOV), bleeding veins in the lower end of the food-pipe in people with serious liver disease. When the liver is diseased, there is less blood flowing through it. This causes the blood to 'back up' in the veins in the lower end of the food pipe (and upper part of the stomach). The veins in the lining of the food pipe (and stomach) then become very large and stretched, much like varicose veins. Because the veins are also very fragile, they can rupture and then bleed severely into the stomach.

GLYPRESSIN contains terlipressin, a substance which acts to stop the bleeding by lowering the blood pressure in the veins of the food-pipe.

GLYPRESSIN is also used to treat hepatorenal syndrome, type 1 (HRS-1). GLYPRESSIN is given when a patient with HRS-1 is being considered for a liver transplant. HRS-1 is a condition in which the kidneys suddenly fail to work in a person with severe liver disease. HRS-1 is a life-threatening complication of severe liver disease.

The cause of HRS-1 is not fully understood. It is thought to be due to the kidneys drastically reducing their own blood flow, in response to large changes in blood flow in other parts of the body caused by severe liver disease.

GLYPRESSIN works in HRS-1 by improving the blood flow in the kidneys.

Ask your doctor if you have any questions about why GLYPRESSIN has been prescribed for you. Your doctor may have prescribed it for another reason.

GLYPRESSIN is not addictive.

This medicine is available only with a doctor's prescription.

Before you are given GLYPRESSIN

When you must not be given it

Do not use GLYPRESSIN if you have an allergy to terlipressin, the active ingredient, or to any of the other ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to GLYPRESSIN may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not use GLYPRESSIN if you are pregnant. It may affect your developing baby if you are given it during pregnancy.

Do not use GLYPRESSIN if you are breast-feeding or planning to breast-feed. It is not known if it passes into breast milk or is safe for use in infants.

Do not use GLYPRESSIN if you currently have heart disease or have recently had heart disease.

Do not use GLYPRESSIN after the expiry date (EXP) printed on the pack.

If you use it after the expiry date has passed, it may not work as well.

Do not use GLYPRESSIN if the packaging is torn/damaged or shows signs of tampering.

Before you are given it

Tell your doctor if you have allergies to:

  • any of the ingredients listed at the end of this leaflet
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • heart disease
  • high blood pressure
  • irregular heartbeat
  • circulation problems
  • kidney problems
  • you are on a controlled sodium diet (this medicine contains 1.33 mmol (or 30.7 mg) of sodium per ampoule)

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you start taking GLYPRESSIN.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and GLYPRESSIN may interfere with each other. These include:

  • beta blockers - used to treat high blood pressure and certain heart conditions
  • propofol, a short-acting anaesthetic
  • sufentanil, a powerful opioid painkiller (not available in Australia).

Taking GLYPRESSIN with these medicines may cause your heart to slow down or beat irregularly.

These medicines may be affected by GLYPRESSIN, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor immediately if you take any of the following medicines:

Medicines that can trigger irregular beating of the heart (known as arrythmia) such as:

  • quinidine, procainamide, disopyramide (Known as Class 1A anti-arrhythmic medicines)
  • amiodarone, sotalol, ibutilide, dofetilide (known as Class III anti-arrhythmic medicines)
  • Erythromycin (an antibiotic)
  • Antihistamines (mainly used to treat allergies and may also be found in certain cough and cold remedies)
  • Anti-depressants known as 'tricyclic antidepressants'
  • Medicines that may change the level of salt or electrolytes in your blood such as diuretics (medicines used to treat high blood pressure and heart failure)

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking GLYPRESSIN.

How GLYPRESSIN is given

How much you will be given

GLYPRESSIN is a medicine that is used in hospital and should only be administered by your doctor or nurse.

Your doctor will give you the correct amount of GLYPRESSIN.

Your doctor may adjust the dose depending on how you are responding to the treatment.

The maximum dose is 1.7 mg every 4 hours (BOV) or every 6 hours (HRS-1).

Instructions for proper use of the drug intended for your doctor or nurse are included in the package insert.

How it is given

GLYPRESSIN will be given to you by injection in one of your veins.

How often it is given

GLYPRESSIN is usually given for up to 48 hours BOV.

GLYPRESSIN is generally used for up to 2 weeks or less in treating an occurrence of HRS-1.

If you are given too much (overdose)

As GLYPRESSIN is given to you by a nurse and under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience any side effects after you are discharged, immediately telephone your doctor, or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766), or go to Accident and Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you receive too much GLYPRESSIN, you may experience any of the following:

  • headache
  • pale skin
  • blue lips and fingernails
  • stomach pain or discomfort
  • nausea
  • diarrhoea.

While you are using GLYPRESSIN

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are or have been treated with GLYPRESSIN.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are or have been treated with GLYPRESSIN.

Be sure to keep all your doctor's appointments. Your doctor will want to do blood and other tests regularly to check on your progress and detect any unwanted side effects.

If you become pregnant while you are being given this medicine, stop taking/using it and tell your doctor, nurse or pharmacist immediately.

Things that may help your condition

Some self-help measures suggested below may help your condition.

Talk to your doctor or pharmacist about them:

  • alcohol - your doctor may advise you to limit your alcohol intake
  • diet - eat a healthy diet which includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar
  • smoking - your doctor may advise you to stop smoking or at least cut down.

Side effects

Tell your doctor or nurse immediately if you do not feel well after you have GLYPRESSIN.

Like all medicines, GLYPRESSIN can have side effects, although not everybody gets them. Sometimes the side effects can be serious, although most of the time they are not. You may need medical attention if you get some of the side effects.

The hospital staff will be monitoring you for possible side effects. If you get some of the side effects, your doctor and/or nurse will help you manage them while you are in the hospital.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Don't be alarmed by the following list of side effects. You may not experience any of them.

The most frequently reported side effects are:

  • headache
  • increased blood pressure
  • slow, fast or irregular heart beat
  • pale skin
  • blue lips and fingernails
  • stomach pain or discomfort
  • diarrhoea.

Other side effects include:

  • local irritation at the injection site
  • difficulty breathing
  • hot flushes
  • chest pain
  • heart failure
  • feeling or being sick (nausea or vomiting)
  • swelling due to excess fluid in the body

Tell your doctor or nurse if you notice anything else that is making you feel unwell.

Other side effects, not listed above, may also occur in some people.

After using GLYPRESSIN

If you have any queries about any aspect of your medicine, or any questions regarding the information in this leaflet, discuss them with your doctor, nurse or pharmacist.

Product description

What it looks like

GLYPRESSIN is given as intravenous injection:

Solution for Injection

  • this is a clear, colourless solution containing 8.5mL of GLYPRESSIN solution (in an ampoule)
  • available in a box containing 5 ampoules of GLYPRESSIN solution.

Ingredients

Active ingredient:
The active ingredient in GLYPRESSIN preparations is terlipressin.

Each ampoule of GLYPRESSIN Solution for Injection contains 0.85 mg terlipressin (equivalent to 1 mg of terlipressin acetate) in 8.5 mL solution.

Other ingredients:
Sodium chloride, Acetic acid, Sodium acetate trihydrate, Water for Injections

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

GLYPRESSIN is supplied in Australia by:

Ferring Pharmaceuticals Pty Ltd
ABN No. 87003 037 170
Suite 2, Level 1, Building 1
20 Bridge Street
Pymble 2073 NSW
Toll free: 1800 337 746
www.ferring.com.au

Australian Register Number(s):

GLYPRESSIN Solution for Injection, ampoule:

AUST R 177708

Date of preparation

This leaflet was prepared in August 2020

DOCS#28327-v7

® Registered Trademark of Ferring

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Glypressin Solution

Active ingredient

Terlipressin

Schedule

S4

 

1 Name of Medicine

Terlipressin (as terlipressin acetate).

2 Qualitative and Quantitative Composition

Terlipressin is freely soluble in water. Although the active ingredient is terlipressin, the drug substance included in this product contains non-stoichiometric amounts of acetic acid and water, and this material is freely soluble in water.
One ampoule of Glypressin contains 0.85 mg terlipressin (equivalent to 1 mg terlipressin acetate) in 8.5 mL of solution. The concentration of terlipressin is 0.1 mg/mL (equivalent to terlipressin acetate 0.12 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection. Clear, colourless liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Glypressin is indicated for the:
treatment of bleeding oesophageal varices;
treatment of patients with hepatorenal syndrome (HRS) Type 1 who are actively being considered for liver transplant.

4.2 Dose and Method of Administration

Method of administration.

Glypressin must only be administered intravenously.
Bleeding oesophageal varices (BOV).

Adults.

Initially an i.v. injection of 1.7 mg terlipressin (2 mg terlipressin acetate) is given every 4 hours. When the bleeding is under control the dose can be adjusted to 0.85 mg terlipressin (1 mg terlipressin acetate) i.v. every 4 hours. After the initial dose, the dose can also be adjusted to 0.85 mg (1 mg terlipressin acetate) i.v. every 4 hours in patients with body weight < 50 kg or if adverse effects occur. The treatment should not continue for more than 48 hours in total.

Children and elderly.

No data are available regarding dosage recommendations in these patient populations.
Hepatorenal syndrome (HRS). 0.85 mg terlipressin every 6 hours by slow intravenous bolus injection for 7 to 14 days (administered in association with albumin 20% 100 mL i.v. twice daily for 7 to 14 days).
If serum creatinine (SCr) has not decreased by at least 30% from the baseline value after 3 days, the dose can be increased to a maximum of 1.7 mg terlipressin every 6 hours.
It is however recommended that the dose not be increased in patients with severe pre-existing cardiovascular disease or in the presence of an ongoing significant adverse event e.g. pulmonary oedema, ischaemia (see Section 4.4 Special Warnings and Precautions for Use). Treatment should be continued until about 2 days after the patient achieves HRS reversal (SCr less than or equal to 132.6 micromol/L) or be discontinued if the patient undergoes dialysis or liver transplant or if SCr remains at or above baseline after 7 days of treatment.
Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction. When the patient's symptoms resolve, Glypressin may be re-commenced at a lower dose or at a less frequent dosing interval (e.g. every 8-12 hours). Lowest doses used in the clinical studies ranged from 1.7 to 2.55 mg terlipressin/day. The maximum dose studied (TAHRS Study) was 1.7 mg terlipressin every 4 hours.

4.3 Contraindications

Pregnancy.
Hypersensitivity to terlipressin or any of the excipients listed in Section 6.1 List of Excipients.
In patients with current or recent ischaemic cardiovascular disease.

4.4 Special Warnings and Precautions for Use

Cardiovascular effects.

Terlipressin should only be used with caution and under strict monitoring of the patients in the following cases:
uncontrolled hypertension;
cerebral or peripheral vascular diseases;
cardiac arrhythmias;
coronary artery disease or previous myocardial infarction.
Terlipressin should not be used in patients with unstable angina or recent acute myocardial infarction.
Caution should be exercised in patients with a history of ischaemic cardiovascular disease since terlipressin may induce ischaemic and cardiovascular events.

Torsade de pointes.

During post-marketing experience, cases of QT interval prolongation and ventricular arrhythmias including "Torsade de pointes" have been reported. In most cases, patients had predisposing factors such as basal prolongation of the QT interval, electrolyte abnormalities (hypokalaemia, hypomagnesaemia) or medications with concomitant effect on QT prolongation. Therefore, extreme caution should be exercised in the use of terlipressin in patients with a history of QT interval prolongation, electrolytic abnormalities, concomitant medications that can prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants or medications that can cause hypokalaemia or hypomagnesaemia (e.g. some diuretics) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cutaneous ischaemic events.

To avoid local necrosis the injection must be administered intravenously.
During post-marketing experience several cases of cutaneous ischemia and necrosis unrelated to the injection site have been reported. Patients with peripheral venous hypertension or morbid obesity seem to have a greater tendency to this reaction. Therefore, extreme caution should be exercised when administering terlipressin in these patients.

Respiratory effects.

Terlipressin may cause smooth muscle constriction and should be used with caution and under strict monitoring in patients with severe asthma or chronic obstructive pulmonary disease (COPD).

Use in renal impairment.

As data are limited terlipressin should be used with caution and under strict monitoring of the patients in renal impairment.

Laboratory monitoring.

During treatment with terlipressin serum creatinine should be monitored at least daily as terlipressin should be used with caution in patients with renal insufficiency.
Fluid balance and electrolytes should be monitored carefully as hyponatraemia, hypokalaemia, hypomagnesaemia and other electrolyte disturbances have been reported.

Excipients.

This medicinal product contains 1.33 mmol (or 30.7 mg) of sodium per ampoule which should be taken into consideration in patients on a controlled sodium diet.

Use in the elderly.

Because of limited experience, special precaution should be taken during treatment of elderly patients. No data are available regarding dosage recommendation in this special patient category.

Paediatric use.

Because of limited experience, special precaution should be taken during treatment of children. No data are available regarding dosage recommendation in this special patient category.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Terlipressin increases the hypotensive effect of non-selective β-blockers on the portal vein. Concomitant treatment with drugs which are known to induce bradycardia (e.g. propofol, sufentanil) may lower the heart rate and cardiac output. These effects are due to reflexogenic inhibition of cardiac activity via the vagus nerve due to elevated blood pressure.
Terlipressin can trigger ventricular arrhythmias including "Torsade de pointes" (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, extreme caution should be exercised in the use of terlipressin in patients with concomitant medications that can prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants or medications that may cause hypokalaemia or hypomagnesemia (e.g. some diuretics).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effects of terlipressin on male or female fertility. In a rat fertility study, mating of terlipressin-treated males (3 weeks prior to mating at 1.8 and 3.6 mg/m2/day i.v.; ca. 25-50% of the Maximum Recommended Daily Human Dose) with untreated females had no effect on the number of matings and frequency of insemination but led to decreased litter size. In a separate study, testicular atrophy and disturbances of spermiogenesis were observed in male rats treated with terlipressin for 3 weeks at 3.6 mg/m2/day i.v. Based on animal studies, there is some risk of reduced fertility in persons taking terlipressin.
(Category D)
Treatment with terlipressin is contraindicated in pregnancy.
Terlipressin is known to cause uterine contractions and increased intrauterine pressure in early pregnancy and may decrease uterine blood flow in humans. Terlipressin may have harmful effects on the pregnancy and the fetus.
Spontaneous abortion and fetal malformations were observed in pregnant rabbits treated with terlipressin throughout organogenesis at i.v. doses (based on body surface area) less than the maximum recommended human daily dose.
 There are no human or animal data on the excretion of terlipressin into milk or on the safety of terlipressin in infants. Hence, terlipressin should not be used in women who are breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

The reporting of safety data rely on published literature and post-marketing surveillance.

Clinical trials.

Three studies assessed safety as primary outcome in totally 1341 patients.
Caletti 1991, a prospective, uncontrolled observational study, enrolled 1258 patients. 21% of the patients experienced a side-effect. The side-effects reported were consistent with the known pharmacological actions of terlipressin.
Bruha 2009, a randomised, double-blind study enrolled 25 patients that were randomised to either 5-day or 10-day treatment. Serum sodium and serum creatinine decreased in both arms during treatment, but rose again after discontinuation of treatment.
Sola 2010, a retrospective cohort study, included 58 patients. Over a 5 day treatment period 67% of the patients developed acute reduction in serum sodium. The hyponatraemia was found to develop rapidly after start of therapy, but was usually reversible with a median recovery time of 4 days after discontinuation of terlipressin.

Post-marketing experience.

The most commonly reported affected system organ classes were: cardiac disorders (66 reactions); vascular disorders (50 reactions); skin and subcutaneous tissue disorders (34 reactions); gastrointestinal disorders (30 reactions); metabolism and nutrition disorders (26 reactions) and nervous system disorders (22 reactions). Table 1 lists the adverse effects reported for terlipressin in the post-marketing period.

Reporting suspected adverse events.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

The recommended dose of 1.7 mg (equivalent to 2 mg terlipressin acetate) every 4 hours should not be exceeded as the risk of severe circulatory adverse effects is dose-dependent.
Elevated blood pressure in patients with recognised hypertension can be controlled with 150 mcg clonidine i.v.
Bradycardia requiring treatment should be treated with atropine.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Terlipressin belongs to the pharmacotherapeutic group: Posterior pituitary lobe hormones (vasopressin and analogues), ATC code: H01B A04.
Terlipressin is a dodecapeptide that has three glycyl residues attached to the N-terminal of lysine vasopressin (LVP). Terlipressin acts as a pro-drug and is converted via enzymatic cleavage of its three glycyl residues to the biologically active lysine vasopressin. A large body of evidence has consistently shown that terlipressin given at doses of 0.85 mg and 1.7 mg respectively (equivalent to terlipressin acetate 1 mg and 2 mg respectively) can effectively reduce the portal venous pressure and produces marked vasoconstriction. The lowering of portal pressure and azygos blood flow is dependent on dose. The effect of the low dose is reduced after 3 hours, while haemodynamic data show that 1.7 mg terlipressin (2 mg terlipressin acetate) is more effective than 0.85 mg (1 mg terlipressin acetate), as the higher dose produces a dependable effect throughout the period of treatment (4 hours).
The primary pharmacodynamic effects of terlipressin are the vasoconstrictive effects mediated through V1a receptors on vascular smooth muscle in the splanchnic and portal circulation. Moreover, terlipressin can also act via V1a receptors to increase systemic mean arterial pressure and cause a reflexogenic heart rate reduction. Regarding secondary pharmacodynamic effects, terlipressin has shown minimal effects on the fibrinolytic system in cirrhotic patients acting on V2 receptors. V2 mediated antidiuretic effects have been observed with terlipressin corresponding to 3% of the native vasopressin. No consistent effect on serum sodium has been seen in healthy volunteers but there may be a potential risk for hyponatremia associated with terlipressin when treating patients with portal hypertension and actively bleeding oesophageal varices. No influence of V1b receptors has been observed as illustrated by no significant effects observed on adrenocorticotropic hormone and cortisol release.

Clinical trials.

Bleeding oesophageal varices (BOV). The data evaluated for this indication were from a literature-based submission which uncovered 28 efficacy publications, including 8 that were published since the 2003 Cochrane Review. Several pharmacokinetic and dose ranging studies were also provided. Twenty-two other publications as well as post-marketing reports and a 1991 paper on post-marketing experience, and 127 literature references were also included.
The studies that contribute the most to demonstrating the efficacy of terlipressin in bleeding oesophageal varices are four pivotal, placebo-controlled studies (Walker et al, 1986; Freeman et al, 1989; Söderlund et al, 1990; Levacher et al, 1995) and two supportive, controlled studies involving endoscopic treatment (Escorsell et al, 2000; Abid et al, 2009). Several other controlled studies provide further supportive evidence. In both the pivotal and supporting studies there was a consistently high rate of bleeding control with terlipressin, despite substantial differences in study design, the dose used and assessment of treatment effect. All doses in the clinical trials section below are stated as 1 mg or 2 mg terlipressin to mean 1 mg or 2 mg terlipressin acetate.

Placebo-controlled studies.

The study of Walker et al. (1986) was a randomised, double-blind, placebo-controlled study of terlipressin as an addition to standard therapy, in cirrhotic patients with endoscopically verified variceal bleeding. After endoscopy, patients were randomised to treatment with either an initial 2 mg i.v. injection of terlipressin, followed by a 1 mg injection every 4 h for a total of 36 h of treatment, or to corresponding placebo. A total of 50 bleeding episodes in 34 patients were randomised; all re-randomised patients had been discharged between randomisations.
The primary efficacy endpoint of control of bleeding within 36 h was met in 25/25 (100%) of the episodes randomised to terlipressin, compared to 20/25 (80%) of the episodes randomised to placebo (p < 0.05). A total of 5/25 (20%) of the episodes randomised to terlipressin were considered treatment failures (including episodes requiring balloon tamponade or sclerotherapy), in contrast to 12/25 (48%) episodes randomised to placebo (p < 0.05). There were no statistically significant differences between the treatment groups in the secondary endpoints of blood and plasma transfusion requirements, duration of bleeding, rebleeding after 36 h of treatment, or in-hospital mortality (terlipressin: 3 deaths/25 episodes, 12%; placebo: 8 deaths/25 episodes, 32%, n.s.).
The study of Freeman et al. (1989) was a randomised, double-blind, placebo-controlled study of terlipressin in patients with portal hypertension and endoscopically verified variceal bleeding. After endoscopy, patients were randomised to treatment with either an initial 2 mg i.v. injection of terlipressin, followed by a 2 mg injection every 4 h for a total of 24 h of treatment (or at least 8 h after the bleeding stopped), then a 1 mg injection every 4 h for an additional 16 h; or to corresponding placebo. A total of 31 bleeding episodes in 29 patients were randomised.
The primary efficacy endpoint of initial control of bleeding without the need for balloon tamponade/ rescue sclerotherapy was met in 9/15 (60%) of the episodes randomised to terlipressin, compared to 6/16 (37%) of the episodes randomised to placebo (n.s.). During follow-up, 1 patient in the terlipressin group and 3 patients in the placebo group had rebleedings (all were successfully controlled by rescue sclerotherapy), leaving 8/15 (53%) of the episodes randomised to terlipressin and 3/16 (19%) of the episodes randomised to placebo as being successfully controlled at 5 days (secondary endpoint; p < 0.05). There were no statistically significant differences between the treatment groups in the further secondary endpoints of blood transfusion requirement or in-hospital mortality (terlipressin: 3 deaths/15 episodes, 20%; placebo: 4 deaths/16 episodes, 25%).
The study of Söderlund et al. (1990) was a randomised, double-blind, placebo-controlled study of terlipressin in cirrhotic patients with endoscopically verified variceal bleeding. After endoscopy, patients were randomised to treatment with either an initial 2 mg i.v. injection of terlipressin, followed by a 2 mg injection every 4 h for a total of 24 to 36 h of treatment, or to corresponding placebo. Treatment was discontinued with a control endoscopy (including sclerotherapy) between 24 and 36 h after the initiation of treatment, or until emergency intervention (e.g. balloon tamponade) was required. A total of 60 patients were randomised; no patient was randomised more than once.
The primary efficacy endpoint of initial control of bleeding without emergency intervention ('success') was met in 28/31 (90%) of the patients randomised to terlipressin, and in 17/29 (59%) of the patients randomised to placebo (p = 0.0067; Fisher's exact test). During treatment, 2 patients in the terlipressin group and 1 patient in the placebo group had rebleedings, thus the secondary endpoint of 'efficacy' (defined as absence of blood in two consecutive gastric rinses, and no ongoing bleeding/ fresh blood at control endoscopy) was met in 26/31 (84%) of the patients in the terlipressin group and in 16/29 (55%) of the patients in the placebo group (p = 0.024; Fisher's exact test). During treatment, transfusion requirements were statistically significantly lower in the terlipressin group than in the placebo group. During the whole study, from first injection to 24-hour follow-up, 22/31 (71%) of the patients in the terlipressin group and 28/29 (97%) of the patients in the placebo group required any blood transfusion (p < 0.05). In-hospital mortality was 3/31 (10%) of the patients in the terlipressin group and 11/29 (38%) of the patients in the placebo group (p < 0.05).
The study of Levacher et al. (1995) was a randomised, double-blind, placebo-controlled study of the combination of terlipressin and nitroglycerin, in cirrhotic patients with upper GI bleeding as diagnosed by gastric lavage. Patients were randomised by an emergency team in the home setting, to treatment with either terlipressin (an initial injection of 1 mg for patients < 50 kg, 1.5 mg for patients 50-70 kg, or 2 mg for patients > 70 kg; patients received repeat injections at 4 h and 8 h) and a transdermal nitroglycerin patch (24 mg/12 h), or to corresponding placebo injections and excipient patch. After initiation of treatment, patients were transferred to the hospital intensive care unit. Concurrent treatments in both treatment groups included endoscopic sclerotherapy, but this was not necessarily performed before the primary efficacy evaluation (control of bleeding at 12 h).
A total of 85 bleeding episodes in 77 patients were randomised; all re-randomised patients had at least 30 days between bleeding episodes. One patient had been included by 'error', therefore the analysis was performed on 84 bleeding episodes in 76 patients.
The primary efficacy endpoint of control of bleeding (without rebleeding) at 12 h was met in 29/41 (71%) of the episodes randomised to terlipressin, and in 20/43 (47%) of the episodes randomised to placebo (p < 0.05). There was no statistically significant difference between the treatment groups in the secondary endpoint of frequency of rebleeding after 12 h; however, the episodes randomised to terlipressin required fewer blood transfusions than episodes randomised to placebo (a mean of 0.79 versus 1.9 units/day; p < 0.05). Mortality was lower in the episodes randomised to terlipressin than in those randomised to placebo at 15 days (8/41, 20% vs. 18/43, 42%; p < 0.05) but not at 42 days (12/41, 36% vs. 20/43, 47%; n.s.). When adjusting for Child-Pugh class, the difference in mortality was statistically significant in favour of terlipressin also at 42 days; in all episodes not classified as Child-Pugh C, the patient survived.

Study versus endoscopic treatment.

The study of Escorsell et al. (2000) was a randomised, non-blinded study of terlipressin versus endoscopic sclerotherapy in cirrhotic patients with endoscopically verified bleeding oesophageal varices. During diagnostic endoscopy, patients were randomised to treatment with either terlipressin (initial 2 mg i.v. injection followed by 2 mg injections every 4 h for 48 h or until control of bleeding was achieved, followed by 1 mg injections every 4 h for 5 more days) or endoscopic sclerotherapy (one immediate intra-paravariceal injection of 5% ethanolamine or 1% polidocanol; no further sclerotherapy until at least one study endpoint was reached). A total of 219 patients were randomised; no patient was randomised more than once.
The primary efficacy endpoint of initial control of bleeding within 48 h was met in 85/105 (81%) patients randomised to terlipressin and in 94/114 (82%) of the patients randomised to sclerotherapy (n.s.). The secondary endpoint of early rebleeding (within 5 days) occurred in 15 patients (14%) in the terlipressin group and in 16 patients (14%) in the sclerotherapy group (n.s.). There were no statistically significant differences between the treatment groups in transfusion requirements, length of hospitalisation (including ICU stay), need for alternative therapy, or the frequency of late rebleeding (terlipressin, 26/105 patients, 25%; sclerotherapy, 29/114 patients, 25%). The 42-day mortality rates were similar between treatment groups (terlipressin, 29/105 patients, 28%; sclerotherapy, 19/114 patients, 17%; n.s).

Study versus active comparator, in addition to endoscopic treatment.

The study of Abid et al. (2009) was a randomised, double-blind non-inferiority study of terlipressin or octreotide as additions to endoscopic banding ligation, in cirrhotic patients with endoscopically verified oesophageal variceal bleeding. On admission but before diagnostic endoscopy, patients were randomised to treatment with either terlipressin (initial 2 mg i.v. injection followed by 1 mg injections every 6 h for a total of 72 h of treatment) or with octreotide (initial 100 microgram i.v. injection and 50 microgram/h infusion for a total of 72 h); both treatment groups received mock placebo treatments. All patients had endoscopic banding ligation within 24 h. A total of 359 patients were randomised before diagnostic endoscopy. Of these patients, 35 were excluded from analysis due to violation of inclusion/ exclusion criteria. Thus, 324 patients with endoscopically confirmed oesophageal variceal bleeding were included in the ITT analysis.
The primary efficacy endpoint of control of bleeding (according to Baveno III criteria) within 72 h was met in 158/163 (97%) of the patients randomised to terlipressin + banding ligation, and in 160/161 (99%) of the patients randomised to octreotide + banding ligation (n.s.). Based on a prespecified non-inferiority margin of 11% for the lower limit of the 95% confidence interval, it was concluded that terlipressin + banding ligation was non-inferior to octreotide + banding ligation. The mean length of hospitalisation was shorter in the terlipressin group than in the octreotide group (108 h vs. 126 h, p < 0.001). In-hospital mortality was 9/163 (6%) in the terlipressin group and 7/161 (4%) in the octreotide group (n.s.).

Duration of treatment.

In the placebo-controlled studies, treatment duration up to the primary efficacy endpoint varied between 12 h and 36 h. The maximum duration of treatment with 2 mg doses (given either every 4 hours or every 6 hours) in any of the evaluated studies was 48 hours (see Section 4.2 Dose and Method of Administration). In those studies where treatment was continued for up to 5 days, a 1 mg dose was used for some or all of the dosing period. A consensus statement from the fifth Baveno Congress (Baveno V) recommends treatment for up to 5 days.
Hepatorenal syndrome (HRS). The efficacy and safety of terlipressin to improve renal function in patients with hepatorenal syndrome type 1 was assessed in one published pivotal study (Sanyal et al. 2008; also known as OT-0401 and NCT00089570) and was supported by another published study (Martin-Llahi et al. 2008; also known as TAHRS and NCT00287664).

Study NCT00089570.

The study of Sanyal et al. (2008) was a prospective, randomised, double-blind, placebo-controlled multicentre, phase III study in 112 HRS type 1 patients who were randomised in a 1:1 ratio to receive either intravenous terlipressin via slow intravenous push at an initial dose of 0.85 mg (as 1 mg terlipressin acetate) every 6 hours or matching placebo for a period of up to 14 days. Dose was increased to 1.7 mg every 6 hours (as 2 mg terlipressin acetate) if serum creatinine had not decreased by at least 30% of baseline value. Equal numbers of patients (88%) in both groups also received intravenous albumin for plasma volume expansion. The mean patient age was 51.7 years, 71.4% were male, 89% were Caucasian. The primary causes of cirrhosis were alcohol (52%) and hepatitis C (37%). Other relevant baseline parameters were (mean): Child-Pugh score 11.5, MELD score 33.4, serum creatinine 3.91 mg/dL [345.6 micromol/L], total bilirubin 15.4 mg/dL [263.3 micromol/L].
Patients were monitored for up to 180 days. The primary endpoint was treatment success at day 14 (defined as serum creatinine (SCr) level ≤ 1.5 mg/dL [132.6 micromol/L] on 2 occasions at least 48 hr apart, without dialysis, death, or recurrence of HRS type 1 on or prior to day 14). The secondary endpoints included change in SCr level from baseline to day 14; HRS reversal (defined as SCr level ≤ 1.5 mg/dL [132.6 micromol/L] during treatment without dialysis); and survival up to 180 days. Treatment outcomes are shown in Table 2, cumulative incidence of HRS reversal in Figure 1.

Survival.

Overall survival at day 180 was not significantly different between the terlipressin (n = 24/56; 43%) and placebo (n = 21/56; 38%) groups (P = 0.839, see Figure 2). Transplant-free survival up to day 180 was also similar in both groups (7/56; 13% for terlipressin vs. 5/56; 9% for placebo). Analysis of overall survival and transplant-free survival for HRS reversal responders vs. non-responders in each treatment group showed a separation in both survival distributions among responders and non-responders. Patients achieving HRS reversal irrespective of treatment, exhibited significantly longer rates of overall survival to day 90 (p = 0.025) and day 180 (p = 0.0073) (Figure 3).

Study NCT00287664 (TAHRS).

The study of Martin-Llahi et al. (2008) was a supportive open-label, comparative multicentre study in 46 patients who were randomised in a 1:1 ratio to receive either intravenous terlipressin (0.85-1.7 mg (as 1 to 2 mg terlipressin acetate) every 4 hours) plus 20% albumin or 20% albumin alone, for a maximum of 15 days. The majority of patients had HRS type 1 (35/46) and the remainder, HRS type 2 (11/46).
The study was terminated prematurely following a protocol specified interim futility analysis of survival and insufficient enrolment. Findings of renal function improvement were consistent with those in the pivotal study of Sanyal et al (2008). There were no significant differences in survival between the two groups, and the causes of death were also similar in both groups.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of terlipressin have been investigated in healthy volunteers and in cirrhotic patients, with similar PK characteristics observed in both populations.

Distribution.

The intravenous pharmacokinetic profile can be described using a two-compartment model with a distribution and elimination half-life of approximately 8 and 40 minutes, respectively. The kinetics of terlipressin is linear with a plasma clearance of about 9 mL/kg/min and a volume of distribution of 0.5 L/kg.
The estimated concentrations of lysine-vasopressin show an initial appearance in plasma 30 minutes after administration of terlipressin with a peak concentration occurring between 60 and 120 minutes. Terlipressin has also been found to be distributed to ascitic fluid, reaching equilibrium with plasma after 60 min.

Metabolism and excretion.

About 1% of the dose administered was excreted unchanged in the urine which indicates almost complete metabolism by peptidases.
Because of a 100% cross-reactivity there is no available RIA-method to differentiate terlipressin from lysine-vasopressin.

5.3 Preclinical Safety Data

Genotoxicity.

Assays for gene mutation and chromosomal damage did not provide any evidence of a genotoxic potential for terlipressin.

Carcinogenicity.

Carcinogenicity studies have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, acetic acid, sodium acetate trihydrate, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

6.3 Shelf Life

2 years.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator at 2°C-8°C in the outer carton to protect from light.

6.5 Nature and Contents of Container

Glypressin Solution for injection, ampoule.

8.5 mL clear, colourless solution in clear glass ampoule, containing 0.85 mg terlipressin (equivalent to 1 mg terlipressin acetate). Supplied in box containing 5 ampoules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


The chemical name is N-[N-(N-Glycylglycyl) glycyl]-8-L-lysinevasopressin.
Terlipressin has an empirical formula of C52H74N16O15S2 and a molecular weight of 1227.4.

CAS number.

14636-12-5. The pKa is approximately 10.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes