Terlipressin Acetate Ever Pharma 0.2 mg/ml solution for injection – patient leaflet, side effects, dosage

1. WHAT TERLIPRESSIN ACETATE 0.2 MG/ML SOLUTION FOR INJECTION IS AND WHAT IT IS USED FOR

Terlipressin acetate 0.2 mg/ml solution for injection contains the active ingredient terlipressin, which is a synthetic pituitary hormone (this hormone is usually produced by the pituitary gland found in the brain).

It will be given to you by injection into a vein.

Terlipressin acetate 0.2 mg/ml solution for injection is used for the treatment of:

• bleeding from dilated (widening) veins in the food pipe leading to your stomach (called bleeding oesophageal varices).
• emergency treatment of type 1 hepatorenal syndrome (rapidly progressive renal failure) in patients with liver cirrhosis (scarring of the liver) and ascites (abdominal dropsy).

2. WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN TERLIPRESSIN ACETATE

0.2 MG/ML SOLUTION FOR INJECTION

You should not receive Terlipressin acetate 0.2 mg/ml solution for injection:

• If you are allergic to terlipressin or any of the other ingredients of this medicine (listed in section 6)

• If you are pregnant.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Terlipressin acetate 0.2 mg/ml solution for injection:

• If you have a severe infection known as septic shock
• If you have bronchial asthma or other conditions that affect your breathing

• If you have uncontrolled high blood pressure, insufficient blood circulation in the heart vessels

  (e.g. angina)

• If you have previously had a heart attack (myocardial infarction), or you have hardening of the arteries (arteriosclerosis)
• If you suffer from seizures (convulsions)

• If you have irregular heart beats (cardiac arrhythmias) or a history of QT interval prolongation

  (disturbance of heart rhythm)

• If you have a poor blood circulation to your brain (e.g. you have had a stroke) or to your limbs (peripheral vascular disease)
• If you have an impaired kidney function (renal insufficiency)
• If you have disturbances in the level of salt (electrolytes) in your blood
• If you have reduced amount of fluid in your circulation or have already lost a large amount of blood
• If you are over the age of 70 years.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before you are given Terlipressin acetate 0.2 mg/ml solution for injection. During treatment with Terlipressin acetate 0.2 mg/ml solution for injection your heart function and fluid and electrolyte balance should be monitored constantly.

Terlipressin acetate 0.2 mg/ml solution for injection can increase your risk of developing respiratory failure (severe breathing difficulties) that may be life-threatening. If you experience difficulty breathing, or symptoms of fluid overload, before Terlipressin acetate 0.2 mg/ml solution for injection is given or during treatment immediately inform your doctor. If you are treated for very severe liver and kidney disease (type 1 hepatorenal syndrome), your doctor should ensure that your heart function and fluid and electrolyte balance are monitored during the treatment.

Particular care is required if you have prior heart or lung disease since Terlipressin acetate 0.2 mg/ml solution for injection can induce heart ischemia (decrease in the amount of blood flow to the heart) and respiratory failure.

Treatment with Terlipressin acetate 0.2 mg/ml solution for injection should be avoided if you have liver failure with multiple organ failures and/or kidney failure with very high levels of creatinine (a waste product) in the blood, as it increases your risk of adverse outcomes. If you are treated for very severe liver and kidney disease, Terlipressin acetate 0.2 mg/ml solution for injection can increase your risk of developing sepsis (bacteria in the blood and the body’s extreme response to an infection) and septic shock (a serious condition that occurs when a major infection leads to low blood pressure and low blood flow). Your doctor will take additional precautions should this apply to you.

Children and adolescents

Terlipressin acetate 0.2 mg/ml solution for injection is not recommended for use in children and adolescents due to insufficient experience.

Other medicines and Terlipressin acetate 0.2 mg/ml solution for injection

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Please inform your doctor immediately if you take any of the following medicines:

• drugs that have an effect on your heart rate (e.g. beta-blockers, sufentanil or propofol)

• drugs that can trigger irregular beating of the heart (arrhythmia) such as the following:

  • anti-arrhythmic drugs known as Class IA (quinidine, procainamide, disopyramide) and

    Class III (amiodarone, sotalol, ibutilide, dofetilide)

  • erythromycin (an antibiotic)
  • antihistamines (mainly used to treat allergies but also found in certain cough and cold remedies)
  • tricyclic antidepressants used to treat depression

  • medicines that may alter the level of salt or electrolytes in your blood, particularly diuretics

    (water tablets used to treat high blood pressure and heart failure) Pregnancy and breast-feeding

Tell your doctor if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby.

Terlipressin acetate 0.2 mg/ml solution for injection must not be used during pregnancy. It is not known if Terlipressin acetate 0.2 mg/ml solution for injection is present in breast milk, therefore the possible effects on your baby are unknown. You should discuss the potential risk to your baby with your doctor.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed. However, if you feel unwell after receiving the injection, do not drive or operate machinery. Terlipressin acetate 0.2 mg/ml solution for injection contains sodium

This medicine contains 3.68 mg sodium (main component of cooking/table salt) in each ml. This is equivalent to 0.18 % of the recommended maximum daily dietary intake of sodium for an adult.

3. HOW TERLIPRESSIN ACETATE 0.2 MG/ML SOLUTION FOR INJECTION WILL

BE GIVEN

This medicine is injected or infused intravenously by a doctor. The doctor will decide the most appropriate dose for you and your heart and blood circulation will be continuously monitored during administration. Please ask your doctor for further information regarding its use. Use in adults

1. 1. Short term management of bleeding oesophageal varices

Initially 1-2 mg terlipressin acetate (5-10 ml of Terlipressin acetate 0.2 mg/ml solution for injection) is given by injection into your vein. Your dose will depend on your body weight. After the initial injection, your dose may be reduced to 1 mg terlipressin acetate (5 ml) every 4 to 6 hours.

1. 2. Type 1 hepatorenal syndrome

The usual dose for injection is 1 mg terlipressin acetate every 6 hours for at least 3 days. If the reduction of serum creatinine is less than 30 % after 3 days of treatment your doctor should consider doubling the dose to 2 mg every 6 hours.

You may also be given Terlipressin acetate 0.2 mg/ml solution for injection as a drip (continuous intravenous infusion) usually starting with 2 mg terlipressin acetate per day and increased in a stepwise manner to a maximum of 12 mg terlipressin acetate per day.

If there is no response to Terlipressin acetate 0.2 mg/ml solution for injection or in patients with complete response, treatment with Terlipressin acetate 0.2 mg/ml solution for injection should be interrupted.

When a reduction in serum creatinine is seen, treatment with Terlipressin acetate 0.2 mg/ml solution for injection should be maintained for a maximum of 14 days.

Use in the elderly

If you are over 70 years of age speak with your doctor before you receive Terlipressin acetate 0.2 mg/ml solution for injection.

Use in patients with kidney problems

Terlipressin acetate 0.2 mg/ml solution for injection should be used with caution in patients with long standing kidney failure.

The following information is intended for healthcare professionals only Posology

1. 1) Short term management of bleeding oesophageal varices:

Initial dose: 1 to 2 mg terlipressin acetate^# (equivalent to 5 to 10 ml solution) is administered by intravenous injection over a period of one minute.

Depending on the patient’s body weight the dose can be adjusted as follows:

• weight less than 50 kg: 1 mg terlipressin acetate (5 ml)
• weight 50 kg to 70 kg: 1.5 mg terlipressin acetate (7.5 ml)
• weight exceeding 70 kg: 2 mg terlipressin acetate (10 ml).

Maintenance dose: After the initial injection, the dose can be reduced to 1 mg terlipressin acetate every 4 to 6 hours.

^# 1 to 2 mg terlipressin acetate corresponding to 0.85 to 1.7 mg terlipressin The approximate value for the maximum daily dose of Terlipressin acetate 0.2 mg/ml solution for injection is 120 micrograms terlipressin acetate per kg body weight.

The therapy is to be limited to 2 to 3 days depending on the response to treatment and the course of the disease.

Terlipressin acetate 0.2 mg/ml solution for injection is injected intravenously and should be given over a period of one minute.

1. 2) In type 1 hepatorenal syndrome:

An i.v. injection of 1 mg terlipressin acetate every 6 hours for at least 3 days. If after 3 days of treatment, the decrease of serum creatinine is less than 30 % with respect to the baseline, doubling the dose to 2 mg every 6 hours will have to be considered.

As an alternative to bolus injection, terlipressin can be administered as a continuous i.v. infusion with a starting dose of 2 mg of terlipressin acetate/24 hours and increased to a maximum of 12 mg of terlipressin acetate/24 hours. Administration of terlipressin as continuous i.v. infusion may be associated with lower rates of severe adverse events than with administration by i.v. bolus.

Example control code (200% scaled)

MASS D = 0,5 mm MASS E = 1,5 mm MASS G = 1,0 mm MASS J = variable MASS F = 8 mm + 2 mm bleed

Color of code must be black

XXXXXXXX

Use in patients with liver problems

No dose adjustment is required in patients with liver failure.

Use in children and adolescents

Terlipressin acetate 0.2 mg/ml solution for injection is not recommended for use in children and adolescents due to insufficient experience.

Duration of treatment

The use of this medicine is limited to 2 – 3 days for short term management of bleeding oesophageal varices and to a maximum of 14 days for treatment of type 1 hepatorenal syndrome, depending on the course of your condition.

If you are given more Terlipressin acetate 0.2 mg/ml solution for injection than you should

As this medicine is given by a healthcare professional, it is unlikely you will be given more than the recommended dose. If you are given too much you may have a rapid increase in your blood pressure (this will be noticed during the continuous monitoring), especially if you already suffer with high blood pressure. If this happens then you will be given another medicine called an alpha blocker (e.g. clonidine) to control your blood pressure.

If you experience lightheadedness, dizziness, or feeling faint, tell your doctor because these could be signs of a low heart rate. This can be treated with another medicine called atropine. If you stop using Terlipressin acetate 0.2 mg/ml solution for injection

Your doctor will advise when it is time to stop receiving this medicine. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them. Important side effects which need immediate attention:

In very rare cases, there may be severe side effects when you are given Terlipressin acetate 0.2 mg/ml solution for injection.

If you are affected by any of the following side effects, please tell your doctor immediately if you are able to. Your doctor should not give you any more Terlipressin acetate 0.2 mg/ml solution for injection.

• severe shortness of breath due to an asthma attack
• severe pain in the chest (angina)
• severe and persistent irregular heart beats
• dead skin around the injection site (necrosis)
• convulsions (seizure)

Tell your doctor or other healthcare professional straight away:

• if you develop breathing difficulties or experience a worsening of breathing ability (signs or symptoms of respiratory failure). This side effect is very common if you are treated for type 1 hepatorenal syndrome - may affect more than 1 in 10 people.
• if you develop signs or symptoms of infection of the blood (sepsis/septic shock), which may include fever and chills or very low body temperature, pale and/or bluish skin, severe breathlessness, urinating less than usual, fast heartbeat, nausea and vomiting, diarrhoea, fatigue and weakness, and feeling dizzy. This side effect is common if you are treated for type 1 hepatorenal syndrome - may affect up to 1 in 10 people.

Other side effects that may occur with different frequencies depending on the disease that you have:

Very common (may affect more than 1 in 10 people):

If you have type 1 hepatorenal syndrome:

• shortness of breath (dyspnoea)

Common (may affect up to 1 in 10 people):

• very slow heart rate
• signs of insufficient blood circulation in the heart vessels in the ECG
• high or low blood pressure
• insufficient blood circulation in arms, legs and skin
• paleness of face
• pale skin
• headache
• temporary abdominal cramps
• temporary diarrhoea
• abdominal cramps (in women)

Tell your doctor or other healthcare professional straight away:

If you have type 1 hepatorenal syndrome:

• fluid in the lungs (pulmonary oedema)
• difficulties in breathing (respiratory distress)

Uncommon (may affect up to 1 in 100 people):

• chest pain
• rapid increase in blood pressure
• heart attack
• too fast heart rate (palpitations)
• swelling of the tissues in the body or fluid on the lungs
• bluish colouration of the skin or lips
• hot flushes
• temporary nausea
• temporary vomiting
• reduced blood supply to the intestinal system
• inflammation of the lymph vessels – seen as fine red streaks under your skin extending from the affected area to the armpit or groin and by fever, chills, headache, and muscle pain
• too little sodium in the blood (hyponatraemia)

Tell your doctor or other healthcare professional straight away:

If you have dilated (widening) veins in the food pipe:

• fluid in the lungs (pulmonary oedema)
• difficulties in breathing (respiratory distress)

Rare (may affect up to 1 in 1,000 people):

• stroke
• too much sugar in the blood (hyperglycaemia)

Tell your doctor or other healthcare professional straight away:

If you have dilated (widening) veins in the food pipe:

• shortness of breath (dyspnoea)

Not known: frequency cannot be estimated from the available data

• heart failure
• Torsade de Pointes
• dead skin (necrosis) in areas other than at the injection site
• decreased blood flow to the uterus
• uterine cramps (cramps in the womb)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE TERLIPRESSIN ACETATE 0.2 MG/ML SOLUTION FOR INJECTION

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

Do not use this medicine after the expiry date which is stated on the carton and the vial after ‘EXP’. The expiry date refers to the last day of that month.

Store in a refrigerator (2˚C-8°C). Do not freeze.

The solution should be inspected visually for particles and discolouration prior to administration. The medicine must not be used if any discolouration is noticed. Do not throw away any medicines via wastewater or household waste. The doctor will dispose of this medicine. These measures will help protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Terlipressin acetate 0.2 mg/ml solution for injection contains

• the active substance is terlipressin acetate.

  5 ml of injection solution contains 1 mg terlipressin acetate corresponding to 0.85 mg terlipressin.

  10 ml of injection solution contains 2 mg terlipressin acetate corresponding to 1.7 mg terlipressin.

  This is equivalent to 0.2 mg terlipressin acetate per ml, corresponding to 0.17 mg terlipessin per ml.

• the other ingredients are: Sodium chloride, acetic acid, sodium hydroxide (for pH-adjustment), hydrochloric acid (for pH-adjustment) and water for injections

What Terlipressin acetate 0.2 mg/ml solution for injection looks like and contents of the pack

This medicine is supplied in a clear glass vial containing 5 ml or 10 ml of a clear, colourless solution.

This medicine is available in pack sizes of: 1 x 5 ml, 5 x 5 ml, 1 x 10 ml, 5 x 10 ml Not all pack sizes may be marketed.

Marketing Authorisation Holder

EVER Valinject GmbH

Oberburgau 3

4866 Unterach am Attersee

Austria

Manufacturer

EVER Pharma Jena GmbH Brüsseler Str. 18

07747 Jena

Germany

This leaflet was last revised in July 2023.

Treatment with terlipressin should be interrupted if there is no response to treatment (defined as decrease of serum creatinine of less than 30 % on day 7 with respect to baseline) or in patients with complete response (values of serum creatinine below 1.5 mg/dl, for at least two consecutive days.

In patients showing an incomplete response (decrease of serum creatinine of at least 30 % with respect to the baseline but without reaching a value below 1.5 mg/dl on day 7), treatment with terlipressin may be maintained for a maximum of 14 days.

In most clinical studies supporting the use of terlipressin for the treatment of hepatorenal syndrome, human albumin was administered simultaneously at a dosage of 1 g/kg BW on the first day and afterwards at a dosage of 20 - 40 g/day.

The usual duration of treatment of hepatorenal syndrome is 7 days, and the maximum duration recommended is 14 days.

Terlipressin acetate 0.2 mg/ml solution for injection should only be used with caution in patients over 70 years, and patients with chronic renal failure.

Type 1 hepatorenal syndrome:

Terlipressin should be avoided in patients with advanced renal dysfunction, i.e., baseline serum creatinine ≥ 442µmol/L (5.0 mg/dL), unless the benefit is judged to outweigh the risks. Terlipressin acetate 0.2 mg/ml solution for injection is not recommended in children and adolescents due to insufficient experience of safety and efficacy.

A dose adjustment is not required in patients with liver failure.

Type 1 hepatorenal syndrome:

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, unless the benefit is judged to outweigh the risks.

Preparation of the injection or infusion

For administration, the required volume should be extracted from the vial with a syringe. Store in a refrigerator (2˚C-8°C). Do not freeze.

For single use only. Discard any unused solution.