Consumer medicine information

Terlipressin Ever Pharma

Terlipressin

BRAND INFORMATION

Brand name

Terlipressin Ever Pharma

Active ingredient

Terlipressin

Schedule

SUMMARY CMI

TERLIPRESSIN EVER PHARMA

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given TERLIPRESSIN EVER PHARMA?

TERLIPRESSIN EVER PHARMA is used to treat Bleeding Oesophageal Varices (BOV) bleeding veins in the lower end of the food pipe in people with serious liver disease. TERLIPRESSIN EVER PHARMA is also used to treat hepatorenal syndrome, type 1 (HRS-1) when a patient with HRS-1 is being considered for a liver transplant. HRS-1 is a life-threatening complication in which the kidneys suddenly fail to work in a person with severe liver disease. TERLIPRESSIN EVER PHARMA contains the active ingredient terlipressin, which is similar to the hormone vasopressin.

For more information, see Section 1. Why am I being given TERLIPRESSIN EVER PHARMA? in the full CMI.

2. What should I know before being given TERLIPRESSIN EVER PHARMA?

Do not use TERLIPRESSIN EVER PHARMA if you have ever had an allergic reaction to terlipressin, or to any of the ingredients listed at the end of the CMI. (see Section 7. Product details in the full CMI.)

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before being given TERLIPRESSIN EVER PHARMA? in the full CMI.

3. What if I am taking other medicines?

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

Some medicines may interfere with TERLIPRESSIN EVER PHARMA and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given TERLIPRESSIN EVER PHARMA?

TERLIPRESSIN EVER PHARMA 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 TERLIPRESSIN EVER PHARMA. Your doctor may adjust the dose depending on how you are responding to the treatment.
Instructions for proper use of the drug intended for your doctor or nurse are included in the package insert.

More instructions can be found in Section 4. How will I be given TERLIPRESSIN EVER PHARMA? in the full CMI.

5. What should I know while being given TERLIPRESSIN EVER PHARMA?

Things you should do

Tell any doctor, dentist or pharmacist you visit that you are being given TERLIPRESSIN EVER PHARMA.
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.

For more information, see Section 5. What should I know while being given TERLIPRESSIN EVER PHARMA? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. Most of them are minor and temporary but some may need medical attention.

Tell your doctor if you experience any side effects including rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty breathing, abnormal heart rhythm and fatigue which may result in developing serious life-threatening conditions (e.g. heart attack). These are very serious side effects. You may need urgent medical attention.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

TERLIPRESSIN EVER PHARMA

Active ingredient: terlipressin (as terlipressin acetate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using TERLIPRESSIN EVER PHARMA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TERLIPRESSIN EVER PHARMA.

Where to find information in this leaflet:

1. Why am I being given TERLIPRESSIN EVER PHARMA?
2. What should I know before being given TERLIPRESSIN EVER PHARMA?
3. What if I am taking other medicines?
4. How will I be given TERLIPRESSIN EVER PHARMA?
5. What should I know while being given TERLIPRESSIN EVER PHARMA?
6. Are there any side effects?
7. Product details

1. Why am I being given TERLIPRESSIN EVER PHARMA?

TERLIPRESSIN EVER PHARMA is used in the treatment of Bleeding Oesophageal Varices (BOV) and in the treatment of hepatorenal syndrome, type 1 (HRS-1) when a patient with HRS-1 is being considered for a liver transplant.

TERLIPRESSIN EVER PHARMA contains the active ingredient terlipressin, which is similar to a natural human hormone vasopressin.

TERLIPRESSIN EVER PHARMA 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. TERLIPRESSIN EVER PHARMA acts to stop the bleeding by lowering the blood pressure in the veins of the food-pipe.

TERLIPRESSIN EVER PHARMA is also given when a patient with hepatorenal syndrome, type 1 (HRS-1) is being considered for a liver transplant. HRS-1 is a life-threatening complication in which the kidneys suddenly fail to work in a person with 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. TERLIPRESSIN EVER PHARMA works in HRS-1 by improving the blood flow in the kidneys.

2. What should I know before being given TERLIPRESSIN EVER PHARMA?

Warnings

TERLIPRESSIN EVER PHARMA should not be used if:

you are allergic to terlipressin, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
you are pregnant or breastfeeding.
you currently have heart disease or have recently had heart disease.

Tell your doctor if you:

have or have had any other medical conditions, especially the following:
- heart disease, including previous heart attack
- high blood pressure
- irregular heartbeat
- blood circulation problems, including diseases affecting the blood vessels in the brain or limbs.
- obesity
- severe asthma or chronic obstructive pulmonary disease (COPD)
- kidney problems
take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not use TERLIPRESSIN EVER PHARMA if you are pregnant or breastfeeding.

It may affect you and your developing baby if you use it during pregnancy. Talk to your doctor immediately if you become pregnant while using TERLIPRESSIN EVER PHARMA.

3. What if I am taking other medicines?

Some medicines may interfere with TERLIPRESSIN EVER PHARMA and affect how it works.

Medicines that have their heart rate lowering effect increased when taken with TERLIPRESSIN EVER PHARMA include:

some beta blockers used to treat high blood pressure and certain heart conditions.
other medicines which slow your heart rate such as propofol, a short-acting anaesthetic.
sufentanil, a powerful opioid painkiller (not available in Australia).

TERLIPRESSIN EVER PHARMA may trigger irregular beating of the heart when taken with:

quinidine, procainamide, disopyramide (known as Class 1A anti-arrhythmic medicines)
amiodarone, sotalol, ibutilide, dofetilide (known as Class III anti-arrhythmic medicines)
erythromycin, an antibiotic
medicines used to treat allergies and may also be found in certain cough and cold remedies (known as antihistamines)
some anti-depressants (known as tricyclic antidepressants)
medicines that may change the level of salt or electrolytes in your blood, such as diuretics or "fluid" medicines (medicines used to treat high blood pressure and heart failure).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect or are affected by TERLIPRESSIN EVER PHARMA.

4. How will I be given TERLIPRESSIN EVER PHARMA?

How much you will be given

TERLIPRESSIN EVER PHARMA is a medicine that is used in hospital and should only be administered intravenously by your doctor or nurse
Your doctor will give you the correct amount of TERLIPRESSIN EVER PHARMA
Your doctor may adjust the dose depending on how you are responding to the treatment
Instructions for proper use of the drug intended for your doctor or nurse are included in the package insert.

When you will be given TERLIPRESSIN EVER PHARMA

When treating BOV, TERLIPRESSIN EVER PHARMA should not continue for more than 48 hours in total.
When treating HRS-1, TERLIPRESSIN EVER PHARMA is usually used for 7-10 days (10 days on average).

How TERLIPRESSIN EVER PHARMA is given

TERLIPRESSIN EVER PHARMA will be given to you by injection in one of your veins.

If you are given too much TERLIPRESSIN EVER PHARMA

As TERLIPRESSIN EVER PHARMA 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, you should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you are given too much TERLIPRESSIN EVER PHARMA, you may experience any of the following:

increased blood pressure
faster heart beats
headache
pale skin
blue lips and fingernails
stomach pain or discomfort
nausea
diarrhoea.

5. What should I know while being given TERLIPRESSIN EVER PHARMA?

Things you should do

Call your doctor straight away if you:

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, tell your doctor, nurse or pharmacist immediately.

Remind any doctor, dentist or pharmacist you visit that you have been given TERLIPRESSIN EVER PHARMA.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects*

Side effects

What to do

Very common side effects (affect more than 1 in 10 users):

difficulty breathing**
stomach (abdominal) pain or discomfort

Common side effects (affect at least 1 in 100 and less than 1 in 10 users):

low blood sodium concentration
headache
chest pain
slow or fast heartbeat
constriction of blood vessels
pale skin
increased blood pressure
blueish colouration of skin and lips
difficulty breathing***
diarrhoea
nausea or vomiting

Uncommon side effects (affect at least 1 in 1000 and less than 1 in 100 users):

abnormal heart rhythm
hot flushes

Side effect with unknown frequency:

uterine constriction
(constriction of the womb)

Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects*

Serious side effects

What to do

Allergic reaction:

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

Myocardial infarction, also known as a heart attack, is a condition when your heart muscle begins to die because it isn't getting enough blood flow (uncommon)
Heart failure (uncommon)
Respiratory failure is a condition when your lungs are not able to get enough oxygen into your blood (very common)** (uncommon)***
Intestinal ischaemia is a condition when there is reduced blood flow to the intestines (uncommon)
Uterine ischaemia is a condition where there is decreased blood flow to the uterus (frequency unknown)
Sepsis/Septic shock is a condition when the body's immune response to an infection causes damage to its own tissue and organs (common)**
Skin necrosis and injection site necrosis are conditions when skin tissue begins to die (uncommon)
Severe and persistent irregular heart rhythm, including Torsade de Pointes (uncommon)
Pulmonary oedema is a condition where there is excess fluid in the lungs (common)**

Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

*Side effects and how often they occur can depend on what you are being given TERLIPRESSIN EVER PHARMA for.

** Applicable to HRS-1

***Applicable to BOV

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines

7. Product details

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

What TERLIPRESSIN EVER PHARMA contains

Active ingredient (main ingredient)	terlipressin (as terlipressin acetate)
Other ingredients (inactive ingredients)	Sodium chloride Glacial acetic acid Sodium hydroxide Hydrochloric acid Water for Injections

Do not take this medicine if you are allergic to any of these ingredients.

What TERLIPRESSIN EVER PHARMA looks like

Clear colourless aqueous solution,

5 mL of injection solution contains 1 mg terlipressin acetate equivalent to 0.85 mg terlipressin.
10 mL of injection solution contains 2 mg terlipressin acetate equivalent to 1.7 mg terlipressin.

Each mL contains 0.17 mg terlipressin equivalent to 0.2 mg terlipressin acetate.

Pack sizes:

1 x 5mL, 5 x 5mL – AUST R 288142

1 x 10mL, 5 x 10mL – AUST R 288156

Who distributes TERLIPRESSIN EVER PHARMA

InterPharma Pty Ltd,
Suite 103,
39 East Esplanade,
Manly NSW 2095,
Australia

This leaflet was prepared in February 2024

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Terlipressin Ever Pharma

Active ingredient

Terlipressin

Schedule

1 Name of Medicine

Terlipressin (as terlipressin acetate).

2 Qualitative and Quantitative Composition

The drug product Terlipressin Ever Pharma contains 0.17 mg/mL terlipressin (anhydrous, acetate free, equivalent to 0.2 mg/mL terlipressin acetate).
The following presentations are available:
0.85 mg/5 mL solution for injection (terlipressin, anhydrous and acetate free);
1.7 mg/10 mL solution for injection (terlipressin, anhydrous and acetate free).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection. Clear, colourless, aqueous sterile solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Terlipressin Ever Pharma solution for injection 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

Terlipressin Ever Pharma solution for injection must only be administered intravenously.
Terlipressin 1.7 mg/10 mL solution for injection vial is intended for the administration of a 1.7 mg dose only.
Product is for single use in one patient only. Discard any unused solution.

Bleeding oesophageal varices (BOV).

Adults.

Initially an i.v. injection of 1.7 mg terlipressin (2 mg terlipressin acetate, equivalent to 10 mL of solution) 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, equivalent to 5 mL of solution) i.v. every 4 hours. After the initial dose, the dose can also be adjusted to 0.85 mg (1 mg terlipressin acetate [5 mL]) i.v. every 4 hours in patients with bodyweight < 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 (5 mL solution) 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 (10 mL solution) 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 maintained until about 2 days after the patient achieves HRS reversal (SCr levels less than or equal to 132.6 micromol/L). Treatment should be discontinued if the patient undergoes dialysis or liver transplantation, if the patient exhibits a partial response (i.e. SCr level does not decrease below 132.6 micromol/L) or if the patient exhibits no response (i.e. no reduction of SCr levels), after 7 days of treatment.
Standard average duration of treatment is 10 days.
Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction. When the patient's symptoms resolve, Terlipressin Ever Pharma 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 other excipients of the product.
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.

Patients with cardiovascular and pulmonary disease.

Particular care is required in management of patients with cardiovascular or pulmonary disease since terlipressin may induce ischaemia and pulmonary vascular congestion.
Caution should also be exercised in treating patients with hypertension.

Monitoring during treatment.

During treatment, regular monitoring of blood pressure, ECG or heart rate, oxygen saturation, serum levels of sodium and potassium, as well as fluid balance are required.

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.

Sepsis/septic shock.

Cases of sepsis/septic shock, including fatal cases, have been reported in patients treated with terlipressin for type 1 HRS. Causal association to terlipressin has not been established. Patients should be monitored daily for any signs or symptoms suggestive of infection.
Terlipressin should not be used in patients with septic shock with a low cardiac output.

Injection site reaction.

To avoid local necrosis, the injection must be administered intravenously.

Skin necrosis.

During post-marketing experience several cases of cutaneous ischemia and necrosis unrelated to the injection site have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with peripheral venous hypertension, diabetes mellitus or obesity seem to have a greater tendency to this reaction. Therefore, extreme caution should be exercised when administering terlipressin in these patients.

Torsades de pointes.

During clinical trials and post-marketing experience, several cases of QT interval prolongation and ventricular arrhythmias including ''torsades de pointes'' have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 or 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).

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).
Fatal cases of respiratory failure, including respiratory failure due to fluid overload, have been reported in patients treated with terlipressin for Type 1 HRS. Patients with a new onset of breathing difficulties or worsening of respiratory disease should be stabilised prior to receiving their first dose of terlipressin.
Caution should be exercised when terlipressin is administered together with human albumin as part of the standard of care for Type 1 HRS. In case of signs or symptoms of respiratory failure or fluid overload, dose reduction of human albumin should be considered. If respiratory symptoms are severe or do not resolve, treatment with terlipressin should be discontinued.

Use in renal impairment.

Prior to treatment of Type 1 HRS, other types of acute kidney injury should be ruled out.
As data are limited terlipressin should be used with caution and under strict monitoring of the patients in renal impairment. Terlipressin should be avoided in patients with advanced renal dysfunction, i.e. baseline serum creatinine ≥ 442 micromoles/L (5.0 mg/dL), when treated with terlipressin for Type 1 HRS, unless the benefit is judged to outweigh the risks. Reduced efficacy in reversal of HRS, increased risk of adverse events, and increased mortality in this patient group have been observed in clinical trials.

Use in hepatic impairment.

Terlipressin should be avoided in patients with severe liver disease defined as Acute-on-Chronic Liver Failure (ACLF) grade 3 and/or a Model for End-stage Liver Disease (MELD) score ≥ 39, when treated with terlipressin for Type 1 HRS, unless the benefit is judged to outweigh the risks. Reduced efficacy in reversal of HRS, increased risk of respiratory failure, and increased mortality in this patient group have been observed in clinical trials.

Use in the elderly.

Because of limited experience, special precaution should be taken during treatment of elderly patients. No data is 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 is 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 "torsades 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

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

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 randomized 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.
There are adverse reactions that appear twice in the table, as the estimated frequencies differ between indications.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 microgram clonidine i.v.
Bradycardia requiring treatment should be treated with atropine.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (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 V_1a receptors on vascular smooth muscle in the splanchnic and portal circulation. Moreover, terlipressin can also act via V_1a 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 V_1b 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; Soderlund 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 Soderlund 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 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 randomized 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 the 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 minutes.

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, glacial acetic acid, sodium hydroxide, hydrochloric acid, water for injections.

6.2 Incompatibilities

Incompatibilities were 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

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 at 2°C to 8°C (Refrigerate. Do not freeze). Store in the outer carton to protect from light.

6.5 Nature and Contents of Container

Supplied in colourless glass vials, closed with rubber stopper and sealed with aluminium flip-off cap.
Each vial contains 5 mL or 10 mL of solution.
Pack sizes: 1 x 5 mL, 5 x 5 mL - AUST R 288142;
1 x 10 mL, 5 x 10 mL - AUST R 288156.

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

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. The pKa is approximately 10.

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.

7 Medicine Schedule (Poisons Standard)

(S4)-Prescription Only Medicine.

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