TERLIPRESINA ACETATE EVER PHARMA 1 mg INJECTABLE SOLUTION

Introduction

Package Leaflet: Information for the User

Terlipressin Acetate EVER Pharma 1 mg Solution for Injection

Terlipressin Acetate

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of thepackage leaflet

1. What is Terlipressin Acetate EVER Pharma and what is it used for
2. What you need to know before you use Terlipressin Acetate EVER Pharma
3. How to use Terlipressin Acetate EVER Pharma
4. Possible side effects
5. Storage of Terlipressin Acetate EVER Pharma
6. Contents of the pack and other information

1. What is Terlipressin Acetate EVER Pharma and what is it used for

Terlipressin Acetate EVER Pharma contains the active substance terlipressin, which is a synthetic pituitary hormone (this hormone is normally produced by the pituitary gland in the brain).

It will be administered by injection into a vein.

Terlipressin Acetate EVER Pharma is used for the treatment of:

• bleeding from enlarged veins (varices) in the tube that carries food 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 (fluid in the abdomen).

2. What you need to know before you use Terlipressin Acetate EVER Pharma

Do not useTerlipressin Acetate EVER Pharma:

• 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

Tell your doctor, pharmacist or nurse before you are given Terlipressin Acetate EVER Pharma:

• if you have a severe infection known as septic shock.
• if you have asthma or other diseases that affect your breathing.
• if you have uncontrolled high blood pressure, poor blood circulation in the heart vessels (e.g. angina pectoris).
• if you have had a heart attack (myocardial infarction) or if you suffer from hardening of the arteries (arteriosclerosis).
• if you have fits (seizures).
• if you have irregular heartbeats (cardiac arrhythmias) or a history of prolongation of the QT interval (heart rhythm disorders).
• if you have poor blood circulation to the brain (e.g. you have had a stroke) or to your limbs (peripheral vascular disease).
• if you have impaired kidney function (renal insufficiency).
• if you have electrolyte disturbances in the blood.
• if you have a decrease in the amount of fluid in the circulation or if you have lost a lot of blood.
• if you are over 70 years old.

If you have any of these conditions (or are unsure), tell your doctor, pharmacist or nurse before you are given Terlipressin Acetate EVER Pharma.

During treatment with Terlipressin Acetate EVER Pharma, your heart function and fluid and electrolyte balance should be monitored.

Terlipressin Acetate EVER Pharma may increase the risk of developing respiratory failure (severe breathing difficulties) that can be fatal. If you experience breathing difficulties or symptoms of fluid overload before or during treatment with Terlipressin Acetate EVER Pharma, tell your doctor immediately.

If you are being treated for 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 treatment. Special care is required if you have pre-existing heart or lung disease, as Terlipressin Acetate EVER Pharma may induce cardiac ischaemia (reduced blood flow to the heart) and respiratory failure. Treatment with Terlipressin Acetate EVER Pharma should be avoided if you have liver failure with multiple organ failures and/or renal failure with very high creatinine levels in the blood, as it increases the risk of adverse outcomes.

If you are being treated for severe liver and kidney disease, Terlipressin Acetate EVER Pharma may increase the risk of developing sepsis (bacteria in the blood and extreme response of the body to an infection) and septic shock (a serious condition that occurs when a major infection causes low blood pressure and reduced blood flow). Your doctor will take additional precautions in your case.

Children and adolescents

Terlipressin Acetate EVER Pharma is not recommended for use in children and adolescents due to insufficient experience.

UsingTerlipressin Acetate EVER Pharmawith other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

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

• medicines that affect heart rate (e.g. beta-blockers, sufentanil or propofol).
• medicines that can cause irregular heartbeats (arrhythmias) such as:

• anti-arrhythmic medicines known as class IA (quinidine, procainamide, disopyramide) and class III (amiodarone, sotalol, ibutilide, dofetilide).
• erythromycin (an antibiotic).
• antihistamines (used mainly to treat allergies, but also present in certain cough and cold preparations).
• tricyclic antidepressants used to treat depression.
• medicines that can alter the level of salt or electrolytes in the blood, especially diuretics (used to remove fluid, in the treatment of hypertension 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 EVER Pharma must not be used during pregnancy.

It is not known whether Terlipressin Acetate EVER Pharma is present in breast milk. Therefore, the potential effects on the baby are unknown. Ask your doctor about the potential risk to the breast-fed child.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed. However, if you do not feel well after the injection, do not drive or operate machinery.

Terlipressin Acetate EVER Pharma contains sodium

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

3. How to take Terlipressin Acetate EVER Pharma

This medicine is injected or infused into a vein by your doctor. Your doctor will decide the most suitable dose for you and will continuously monitor your heart and blood circulation during administration. Ask your doctor for more information about its use.

Use in adults

1. Short-term management of bleeding oesophageal varices.

Initially, 1-2 mg of terlipressin acetate (5-10 ml of Terlipressin Acetate EVER) is administered by injection into a vein. The dose will depend on your body weight.

After the initial injection, the dose may be reduced to 1 mg of terlipressin acetate (5 ml) every 4-6 hours.

1. Type 1 hepatorenal syndrome

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

Terlipressin Acetate EVER Pharma may also be administered as a drip (continuous intravenous infusion) starting normally with 2 mg of terlipressin acetate per day and increasing stepwise up to a maximum of 12 mg of terlipressin acetate per day.

If there is no response to Terlipressin Acetate EVER Pharma, or if patients have a complete response, treatment with Terlipressin Acetate EVER should be discontinued.

When a reduction in serum creatinine is observed, treatment with Terlipressin Acetate EVER Pharma should be maintained for up to a maximum of 14 days.

Use in elderly patients

If you are over 70 years old, ask your doctor before you are given Terlipressin Acetate EVER Pharma.

Use in patients with kidney problems

Terlipressin Acetate EVER Pharma should be used with caution in patients with long-term kidney failure.

Use in patients with liver problems

No dose adjustment is required in patients with liver problems.

Use in children and adolescents

Terlipressin Acetate EVER Pharma 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 the short-term treatment of bleeding oesophageal varices and up to a maximum of 14 days for the treatment of type 1 hepatorenal syndrome, depending on the progression of your disease.

If you are given more Terlipressin Acetate EVER Pharma than you should

As this medicine is administered by a healthcare professional, it is unlikely that you will be given a higher dose than recommended. If you are given too much, you may experience a rapid increase in blood pressure (this will be detected during continuous monitoring), especially if you already have high blood pressure. If this happens, you will be given another medicine called an alpha-blocker (e.g. clonidine) to control blood pressure.

If you experience fainting, dizziness or a feeling of fainting, tell your doctor as these may be symptoms of a slow heart rate. This can be treated with another medicine called atropine.

If you stop treatment with Terlipressin Acetate EVER Pharma

Your doctor will tell you when you should 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 that require immediate attention:

In rare cases, there is a possibility of serious side effects when you are given Terlipressin Acetate EVER Pharma. If you experience any of the following side effects, tell your doctor immediatelyif possible. Your doctor should stop administering Terlipressin Acetate EVER Pharma.

• severe breathing difficulties due to an asthma attack.

• severe chest pain (angina).
• severe and persistent irregular heartbeats.
• dead skin around the injection site (necrosis).
• fits (seizures).

Tell your doctor or another healthcare professional immediately:

• if you develop breathing difficulties or experience a worsening of your breathing ability (signs or symptoms of respiratory failure). This side effect is very common if you are being treated for type 1 hepatorenal syndrome - it may affect more than 1 in 10 people.
• if you develop signs or symptoms of infection in the blood (sepsis/septic shock), which may include fever and chills or low body temperature, pale or blue-tinged skin, severe shortness of breath, decreased urine output, rapid heart rate, nausea and vomiting, diarrhoea, fatigue and weakness, and feeling of dizziness. This side effect is common if you are being treated for type 1 hepatorenal syndrome: it may affect up to 1 in 10 people.

Other side effects that may occur with different frequencies depending on the disease you are suffering from:

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

If you have type 1 hepatorenal syndrome:

• breathing difficulties (dyspnoea).

Common (may affect up to 1 in 10 people)

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

Tell your doctor or another healthcare professional immediately:

If you have type 1 hepatorenal syndrome:

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

Uncommon (may affect up to 1 in 100 people)

• chest pain.
• rapid increase in blood pressure.
• heart attack.
• very fast heart rate (palpitations).
• swelling of body tissues or fluid in the lungs.
• blue-tinged skin or lips.
• hot flushes.
• temporary nausea.
• temporary vomiting.
• poor blood flow to the intestinal system.
• inflammation of the lymph vessels (fine red lines under the skin that extend from the affected area to the armpit or groin and fever, chills, headache and muscle pain).
• low sodium levels in the blood (hyponatraemia).

Tell your doctor or another healthcare professional immediately:

If you have enlarged veins (varices) in the food pipe:

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

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

• stroke.
• high blood sugar levels (hyperglycaemia).

Tell your doctor or another healthcare professional immediately:

If you have enlarged veins (varices) in the food pipe:

• breathing difficulties (dyspnoea).

Not known (frequency cannot be estimated from the available data)

• heart failure.
• Torsade de Pointes.
• dead skin (necrosis) in areas not related to the injection site.
• decreased blood flow to the uterus.
• uterine contractions.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Terlipressin Acetate EVER Pharma

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 vial after EXP. The expiry date is the last day of the month stated.

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

The solution should be inspected visually for particles or discolouration before administration. The medicine should not be used if discolouration is observed.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Package Contents and Additional Information

Composition of Terlipresina acetato EVER Pharma

• The active ingredient is terlipresina acetato.

5 ml of injectable solution contains 1 mg of terlipresina acetato, corresponding to 0.85 mg of terlipresina. This is equivalent to 0.2 mg of terlipresina acetato per ml, corresponding to 0.17 mg of terlipresina per ml.

• The other components are: sodium chloride, acetic acid, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment), and water for injectable preparations.

Appearance of the Product and Package Contents

This medication is presented in transparent glass vials containing 5 ml of a clear and colorless solution.

This medication is available in package sizes: 1 x 5 ml and 5 x 5 ml.

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

EVER Valinject GmbH

Oberburgau 3

4866 Unterach am Attersee

Austria

Manufacturer

EVER Pharma Jena GmbH

Otto-Schott-Strasse 15

07745 Jena

Germany

EVER Pharma Jena GmbH

Brüsseler Str. 18

07747 Jena

Germany

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

EVER Pharma Therapeutics Spain, S.L.

C/Toledo 170

28005 Madrid

Spain

This medication is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Date of the last revision of this prospectus: May 2023

Detailed information about this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended only for healthcare professionals

Dosage

1. Short-term treatment of bleeding esophageal varices:

Initial dose: 1 to 2 mg of terlipresina acetato# (equivalent to 5 to 10 ml of solution) is administered intravenously over one minute.

According to the patient's body weight, the dose may be adjusted as follows:

• weight less than 50 kg: 1 mg of terlipresina acetato (5 ml)
• weight between 50 kg and 70 kg: 1.5 mg of terlipresina acetato (7.5 ml)
• weight over 70 kg: 2 mg of terlipresina acetato (10 ml).

Maintenance dose: after the initial injection, the dose may be reduced to 1 mg of terlipresina acetato every 4 to 6 hours.

# 1 to 2 mg of terlipresina acetato corresponding to 0.85 to 1.7 mg of terlipresina

The approximate value for the maximum daily dose of Terlipresina acetato EVER Pharma is 120 micrograms of terlipresina acetato per kg of body weight.

Treatment should be limited to 2 to 3 days according to the response to treatment in the course of the disease.

Terlipresina acetato EVER Pharma is injected intravenously and should be administered over one minute.

1. Hepatorenal syndrome type 1:

An intravenous injection of 1 mg of terlipresina acetato every 6 hours for a minimum of 3 days. If after 3 days of treatment, the decrease in serum creatinine is less than 3% compared to the initial value, it should be considered to double the dose to 2 mg every 6 hours.

As an alternative to bolus injection, terlipresina can be administered as a continuous intravenous (IV) infusion with an initial dose of 2 mg of terlipresina acetato/24 hours and can be increased up to a maximum of 12 mg of terlipresina acetato/24 hours. The administration of terlipresina as a continuous intravenous infusion may be associated with lower rates of serious adverse reactions than with intravenous bolus administration.

Treatment with terlipresina should be discontinued if there is no response to it (defined as a decrease in serum creatinine of less than 30% on day 7 compared to the baseline value) or in patients with a complete response (serum creatinine values below 1.5 mg/dl for at least two consecutive days.

In patients who showed an incomplete response (decrease in serum creatinine of at least 30% compared to the initial value, but without reaching a value below 1.5 mg/dl on day 7), treatment with terlipresina should be maintained for up to a maximum of 14 days.

In most clinical trials that support the use of terlipresina in the treatment of hepatorenal syndrome, human albumin was administered simultaneously at a dose of 1 g/kg PC on the first day and then at a dose of 20-40 g/day.

The usual duration of treatment for hepatorenal syndrome is 7 days, with a maximum recommended duration of 14 days.

Terlipresina acetato EVER Pharma should be used with caution in patients over 70 years of age and in patients with chronic renal failure.

Hepatorenal syndrome type 1:

Terlipresina should be avoided in patients with advanced renal dysfunction, i.e., basal serum creatinine ≥ 442 μmol/l (5.0 mg/dl), unless it is considered that the benefit outweighs the risks.

Terlipresina acetato EVER Pharma is not recommended for use in children and adolescents due to insufficient safety and efficacy experience.

No dose adjustment is necessary in patients with hepatic insufficiency.

Hepatorenal syndrome type 1:

The use of terlipresina 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 it is considered that the benefit outweighs the risks.

Preparation of the injection or infusion

For administration, the required volume should be withdrawn from the vial with a syringe.

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

For single use. Discard unused solution.