Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Terlipressin acetate EVER Pharma 1 mg solution for injection

terlipressin acetate

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• If you experience any adverse reactions, consult your doctor, pharmacist, or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Terlipresina acetato EVER Pharma is and what it is used for

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

It is administered by injection into a vein.

Terlipresina acetato EVER Pharma is used for the treatment of:

• bleeding from enlarged (dilated) veins in the tube that carries food to the stomach (known as bleeding esophageal varices).
• emergency treatment of hepatorenal syndrome type 1 (rapidly progressive kidney failure) in patients with liver cirrhosis (liver scarring) and ascites (abdominal fluid accumulation).

2. What you need to know before using Terlipressin acetate EVER Pharma

Do not use Terlipressin acetate EVER Pharma:

• if you are allergic to terlipressin or to 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 EVER Pharma:

• If you have a severe infection known as septic shock
• If you suffer from bronchial asthma or other diseases affecting your breathing
• If you have uncontrolled high blood pressure, or insufficient blood circulation in the heart vessels (e.g., angina pectoris)
• If you have previously had a heart attack (myocardial infarction), or if you suffer from hardening of the arteries (arteriosclerosis)
• If you experience seizures (convulsions)
• If you have irregular heartbeats (cardiac arrhythmias) or a history of prolonged QT interval (a heart rhythm disorder)
• If you have poor blood circulation to the brain (e.g., stroke) or to your limbs (peripheral vascular disease)
• If you have impaired kidney function (renal insufficiency)
• If you have disturbances in blood electrolyte levels
• If you have reduced circulating fluid volume or have already lost a large amount of blood
• If you are over 70 years of age.

If you have any of these conditions (or are unsure), inform your doctor, pharmacist, or nurse before receiving Terlipressin acetate EVER Pharma.

During treatment with Terlipressin acetate EVER Pharma, monitoring of cardiac function and fluid and electrolyte balance must be ensured.

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

If you are being treated for severe liver and kidney disease (hepatorenal syndrome type 1), your doctor must ensure that your cardiac function and fluid and electrolyte balance are monitored during treatment. Special caution is required if you have pre-existing heart or lung disease, as Terlipressin acetate EVER Pharma may induce cardiac ischemia (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 failure and/or renal failure with very high levels of creatinine (a waste product) in the blood, as this 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 an extreme systemic response to infection) and septic shock (a serious condition occurring when a severe infection causes low blood pressure and reduced blood flow). Your doctor will take additional precautions in your case.

Children and adolescents

The use of Terlipressin acetate EVER Pharma is not recommended in children and adolescents due to insufficient experience.

Using Terlipressin acetate EVER Pharma with other medicines

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

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

• Medicines affecting heart rate (e.g., beta-blockers, sufentanil, or propofol)

• Medicines that may cause irregular heartbeats (arrhythmias), such as:

  • Antiarrhythmic medicines 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 present in certain cough and cold preparations)
  • Tricyclic antidepressants used to treat depression

• Medicines that may alter blood salt or electrolyte levels, especially diuretics (used to eliminate fluids, in the treatment of hypertension and heart failure)

Pregnancy and breastfeeding

Inform your doctor if you are pregnant or breastfeeding, think you might be pregnant, or plan to become pregnant.

Terlipressin acetate EVER Pharma must not be used during pregnancy.

It is unknown whether Terlipressin acetate EVER Pharma is present in human breast milk. Therefore, possible effects on the infant are unknown. Consult your doctor to discuss the potential risk to the breastfed infant.

Driving and using machines

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

Terlipressin acetate EVER Pharma contains sodium

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

3. How to take Terlipresina acetato EVER Pharma

This medicine is injected or infused intravenously by your doctor. Your doctor will decide the most appropriate dose for you and will continuously monitor your heart and blood circulation during administration. Consult your doctor for further information about its use.

Use in adults

1. Short-term management of bleeding esophageal varices.

Initially, 1–2 mg of terlipressin acetate (5–10 ml of Terlipresina acetato EVER) is administered as an intravenous injection. 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.

2. Type 1 hepatorenal syndrome

The usual 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 should consider doubling the dose to 2 mg every 6 hours.

Terlipresina acetato EVER Pharma may also be administered as a continuous intravenous infusion, typically starting at 2 mg of terlipressin acetate per day, with stepwise increases up to a maximum of 12 mg of terlipressin acetate per day.

If there is no response to Terlipresina acetato EVER Pharma, or if patients achieve a complete response, treatment with Terlipresina acetato EVER should be discontinued.

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

Use in elderly patients

If you are over 70 years old, consult your doctor before receiving Terlipresina acetato EVER Pharma.

Use in patients with kidney problems

Terlipresina acetato EVER Pharma should be used with caution in patients with long-standing renal insufficiency.

Use in patients with liver problems

Dose adjustment is not required in patients with hepatic impairment.

Use in children and adolescents

Terlipresina acetato 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 esophageal varices and up to a maximum of 14 days for the treatment of type 1 hepatorenal syndrome, depending on the course of your disease.

If you are given more Terlipresina acetato EVER Pharma than you should

As this medicine is administered by a healthcare professional, it is unlikely that you will receive more than the recommended dose. If you do receive an excessive amount, you may experience a rapid increase in blood pressure (which will be detected during continuous monitoring), especially if you already have hypertension. If this occurs, you will be given another medicine called an alpha blocker (e.g., clonidine) to control blood pressure.

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

If you interrupt treatment with Terlipresina acetato EVER Pharma

Your doctor will advise you when to stop receiving this medicine.

If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Important adverse effects requiring immediate attention:

In very rare cases, serious adverse effects may occur when Terlipressin acetate EVER Pharma is administered. If you experience any of the following adverse effects, inform your doctor immediately, if possible. Your doctor must stop administering Terlipressin acetate EVER Pharma.

• severe breathing difficulties due to an asthma attack
• acute chest pain (angina)
• severe and persistent irregular heartbeats
• dead skin around the injection site (necrosis)
• seizures (fits)

Immediately inform your doctor or another healthcare professional:

• if you develop breathing difficulties or worsening respiratory function (signs or symptoms of respiratory failure). This adverse effect is very common when being treated for type 1 hepatorenal syndrome – it may affect more than 1 in 10 people.
• if you develop signs or symptoms of blood infection (sepsis/septic shock), which may include fever and chills or very low body temperature, pale and/or bluish skin, severe shortness of breath, reduced urination, rapid heartbeat, nausea and vomiting, diarrhea, fatigue and weakness, and dizziness. This adverse effect is common when being treated for type 1 hepatorenal syndrome – it may affect up to 1 in 10 people.

Other adverse effects that may occur with varying frequency depending on the condition being treated:

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

If you have type 1 hepatorenal syndrome:

• difficulty breathing (dyspnea)

Common (may affect up to 1 in 10 people)

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

Immediately inform your doctor or another healthcare professional:

If you have type 1 hepatorenal syndrome:

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

Uncommon (may affect up to 1 in 100 people)

• chest pain
• rapid increase in blood pressure
• heart attack
• heart beating too fast (palpitations)
• swelling of body tissues or fluid in the lungs
• bluish discoloration of the skin or lips
• hot flushes
• temporary nausea
• temporary vomiting
• insufficient blood flow to the intestinal system
• inflammation of lymphatic vessels (fine red lines under the skin spreading from the affected area to the armpit or groin, accompanied by fever, chills, headache, and muscle pain)
• blood sodium levels too low (hyponatremia)

Immediately inform your doctor or another healthcare professional:

If you have dilated (widened) blood vessels in the gastrointestinal tract:

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

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

• stroke
• blood sugar levels too high (hyperglycemia)

Immediately inform your doctor or another healthcare professional:

If you have dilated (widened) blood vessels in the gastrointestinal tract:

• difficulty breathing (dyspnea)

Not known (frequency cannot be estimated from available data)

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

Reporting of adverse effects

If you experience any type of adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse 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 stated on the packaging and vial after EXP. The expiry date refers to the last day of the month indicated.

Store in a refrigerator between 2°C and 8°C. Do not freeze.

The solution should be inspected visually for the presence of particles or discoloration prior to administration. The medicine should not be used if discoloration is observed.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to properly dispose of any unused medicines and their containers. This helps protect the environment.

6. Contents of the pack and other information

Composition of Terlipressin Acetate EVER Pharma

• The active substance is terlipressin acetate.

5 ml of injectable solution contains 1 mg of terlipressin acetate, equivalent to 0.85 mg of terlipressin. This corresponds to 0.2 mg of terlipressin acetate per ml, equivalent to 0.17 mg of terlipressin per ml.

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

Appearance of the medicinal product and contents of the container

This medicine is presented in clear glass vials containing 5 ml of clear, colourless solution.

This medicine is available in pack sizes of: 1 x 5 ml and 5 x 5 ml.

Only some pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation 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

Further information on this medicine is available upon request by contacting the local representative of the Marketing Authorisation Holder:

EVER Pharma Therapeutics Spain, S.L.

C/Toledo 170

28005 Madrid

Spain

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

AT	Terlipressin acetate EVER Pharma 0.2 mg/ml solution for injection
BG	Терлипресин ацетат EVER Pharma 0,2 mg/ml разтвор за инжекции
CZ	Terlipressin acetate EVER Pharma
DE	Terlipressin acetate EVER Pharma 0.2 mg/ml solution for injection
ES	Terlipressin acetate EVER Pharma 1 mg solution for injection
	Terlipressin acetate EVER Pharma 2 mg solution for injection
FR	ACETATE DE TERLIPRESSINE EVER PHARMA 0.2 mg/ml, solution injectable
IE	Terlipressin acetate EVER Pharma 0.2 mg/ml solution for injection
IT	Terlipressin acetate EVER Pharma
PL	Terlipressin acetate EVER Pharma
PT	Terlipressin acetate EVER Pharma, 0.2 mg/ml, solution for injection
RO	Acetate of Terlipressin EVER Pharma 0.2 mg/ml solution for injection
SK	Terlipressin acetate EVER Pharma 0.2 mg/ml solution for injection
UK	Terlipressin acetate EVER Pharma 0.2 mg/ml solution for injection

Date of the most recent review of this leaflet: May 2023

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

---

This information is intended for healthcare professionals only

Dosage

1. Short-term treatment of bleeding esophageal varices:

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

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

• weight below 50 kg: 1 mg of acetate terlipressin (5 ml)
• weight between 50 kg and 70 kg: 1.5 mg of acetate terlipressin (7.5 ml)
• weight above 70 kg: 2 mg of acetate terlipressin (10 ml).

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

1 to 2 mg of acetate terlipressin corresponding to 0.85 to 1.7 mg of terlipressin

The approximate maximum daily dose of Terlipressin acetate EVER Pharma is 120 micrograms of acetate terlipressin per kg of body weight.

Treatment should be limited to 2 to 3 days depending on the response to treatment during the course of the disease.

Terlipressin acetate EVER Pharma is administered by intravenous injection and must be given over one minute.

2. Type 1 hepatorenal syndrome:

An intravenous injection of 1 mg of acetate terlipressin every 6 hours for a minimum of 3 days. If after 3 days of treatment, the reduction in serum creatinine is less than 3% compared to baseline, the dose should be considered for doubling to 2 mg every 6 hours.

As an alternative to bolus injection, terlipressin may be administered as a continuous intravenous (IV) infusion with an initial dose of 2 mg of terlipressin acetate/24 hours, which may be increased up to a maximum of 12 mg of terlipressin acetate/24 hours. Administration of terlipressin as a continuous intravenous infusion may be associated with lower rates of serious adverse reactions compared to bolus intravenous administration.

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

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

In most clinical trials supporting the use of terlipressin in the treatment of hepatorenal syndrome, human albumin was administered concomitantly at a dose of 1 g/kg body weight on the first day, followed by 20–40 g/day.

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

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

Type 1 hepatorenal syndrome:

Terlipressin should be avoided in patients with advanced renal dysfunction, i.e., baseline serum creatinine ≥ 442 μmol/l (5.0 mg/dl), unless the benefit is considered to outweigh the risks.

Terlipressin acetate EVER Pharma is not recommended for use in children and adolescents due to insufficient safety and efficacy data.

No dose adjustment is necessary in patients with hepatic impairment.

Type 1 hepatorenal syndrome:

The use of 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 considered to outweigh the risks.

Preparation of injection or infusion

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

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

For single use only. Discard any unused solution.