TRABECTEDINE EVER PHARMA 0.25 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Trabectedina EVER Pharma0.25 mg powder for concentrate for solution for infusion EFG.

Trabectedina EVER Pharma 1 mg powder for concentrate for solution for infusion EFG.

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.
• If you experience any side effects, talk to your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the Package Leaflet

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

1. What is Trabectedina EVER Pharma and what is it used for

Trabectedina EVER Pharma contains the active substance trabectedina. Trabectedina EVER Pharma is an anticancer medicine that works by preventing the multiplication of tumor cells.

Trabectedina is used to treat patients with advanced soft tissue sarcoma, when previous treatment with other medicines has not worked or when patients cannot use other medicines. Soft tissue sarcoma is a malignant tumor that starts in some part of the soft tissues, such as muscles, fat, or other tissues (e.g., cartilage or blood vessels).

Trabectedina in combination with pegylated liposomal doxorubicin (PLD, another anticancer medicine) is used to treat patients with ovarian cancer who have relapsed after at least one previous treatment and are not resistant to platinum-containing anticancer medicines.

2. What you need to know before you start using Trabectedina EVER Pharma

Do not use Trabectedina EVER Pharma

• if you are allergic to trabectedina or any of the other ingredients of this medicine

(listed in section 6);

• if you have a severe infection;
• if you are breastfeeding;
• if you are going to receive the yellow fever vaccine.

Warnings and precautions

Talk to your doctor before starting treatment with trabectedina.

You should not use trabectedina or its combination with PLD if you have severe liver, kidney, or heart problems.

Talk to your doctor before starting treatment with trabectedina if you know or suspect that you have:

• Liver or kidney problems.
• Heart problems or a history of heart problems.
• A left ventricular ejection fraction (LVEF) below the lower limit of normal.
• Have received high-dose anthracycline treatment in the past.

Go to your doctor immediately if you experience any of the following:

• If you have a fever, as trabectedina may cause side effects that affect the blood and liver.

• If, despite taking anti-nausea medication, you experience nausea, vomiting, or are unable to drink fluids and therefore urinate less, go to your doctor immediately.

• If you notice severe muscle pain or weakness, as it could be a sign of muscle damage (rhabdomyolysis, see section 4).

• If you notice that the trabectedina infusion is leaking out of the vein during administration. This could damage or destroy the cells of the tissues near the injection site (tissue necrosis, see also section 4), which may require surgical intervention.

• If you experience an allergic reaction (hypersensitivity). In this case, you may experience one or more of the following symptoms: fever, difficulty breathing, redness or rash, feeling of dizziness (nausea) or feeling of discomfort (vomiting, see section 4).

• If you notice swelling or partial swelling without apparent cause (edema), possibly accompanied by dizziness, vertigo, or thirst (low blood pressure). This could be a manifestation of a disorder (capillary leak syndrome) that can cause excessive fluid accumulation in your tissues, requiring urgent clinical evaluation by your doctor.

Children and adolescents

Trabectedina should not be used in children under 18 years of age with pediatric sarcomas.

Other medicines and Trabectedina EVER Pharma

Tell your doctor if you are using, have recently used, or may need to use any other medicine.

You should not use trabectedina if you are going to receive the yellow fever vaccine, and it is not recommended if you are going to receive a vaccine containing live virus particles. The use of medicines containing phenytoin (for the treatment of epilepsy) with trabectedina is not recommended, as the effect of phenytoin may be reduced.

If you use any of the following medicines during your treatment with trabectedina, you need to be closely monitored, as the effects of Trabectedina EVER Pharma are:

• reduced (e.g., using medicines containing rifampicin (for bacterial infections), phenobarbital (for epilepsy), or St. John's Wort (Hypericum perforatum, a medicinal plant used for the treatment of depression)) or

• increased (e.g., medicines containing ketoconazole or fluconazole (for fungal infections), ritonavir (for HIV infection), clarithromycin (for bacterial infections), aprepitant (to prevent nausea and vomiting), cyclosporine (to inhibit the body's defense system), or verapamil (for hypertension and other heart disorders)).

The use of trabectedina with any of these medicines should be avoided if possible.

If, in addition to trabectedina or the combination of Trabectedina and PLD, you are receiving another medicine that can cause liver or muscle damage (rhabdomyolysis), you may be closely monitored, as the risk of liver or muscle damage may increase. Medicines containing statins (to reduce cholesterol levels and prevent cardiovascular disease) are an example of medicines that can cause muscle damage.

Use of Trabectedina EVER Pharma with alcohol

Alcohol consumption should be avoided during treatment with trabectedina, as it may damage the liver.

Pregnancy, breastfeeding, and fertility

Pregnancy

Trabectedina should not be used during pregnancy. If you are pregnant, think you may be pregnant, or plan to become pregnant, consult your doctor before using this medicine.

Women of childbearing age should use effective contraceptive methods during treatment with trabectedina and for up to 3 months after the end of treatment.

If you become pregnant, you should inform your doctor immediately; additionally, genetic counseling is recommended, as trabectedina may cause genetic damage to the fetus.

Breastfeeding

Trabectedina should not be administered to patients who are breastfeeding. Therefore, before starting treatment, you should stop breastfeeding and not resume it until your doctor confirms that it is safe to do so.

Fertility

Men of childbearing age should use effective contraceptive methods during treatment with trabectedina and for up to 5 months after treatment.

Because there is a risk that treatment with trabectedina may cause irreversible infertility, patients are advised to seek counseling on the possibility of preserving their eggs or sperm before treatment.

Genetic counseling is also recommended for patients who wish to have children after treatment.

Driving and using machines

You may feel tired and weak during treatment with trabectedina. Do not drive or use tools or machines if you experience any of these side effects.

Trabectedina EVER Pharma contains sodium

This medicine contains sodium, less than 1 mmol (23 mg) per vial; this is essentially "sodium-free".

3. How to use Trabectedina EVER Pharma

Trabectedina should be administered under the supervision of a doctor with experience in the use of chemotherapy. Its use should be limited to qualified oncologists and other healthcare professionals specialized in the administration of cytotoxic medicines.

For the treatment of soft tissue sarcoma, the usual dose is 1.5 mg/m2 of body surface area. During the treatment period, your doctor will closely monitor you and decide what dose of trabectedina is most suitable for you. The recommended dose in Japanese patients is lower than the usual dose for other races and is 1.2 mg/m2 of body surface area.

For the treatment of ovarian cancer, the usual dose is 1.1 mg/m2 of body surface area after administration of 30 mg/m2 of body surface area of PLD.

Before administration, trabectedina must be reconstituted and diluted for intravenous use. Each time you receive trabectedina for the treatment of soft tissue sarcoma, it will take approximately 24 hours for the entire solution to enter your bloodstream. The treatment of ovarian cancer will last 3 hours.

In order to avoid irritation at the injection site, it is recommended that trabectedina be administered through a central venous line.

In order to protect the liver and reduce the risk of side effects such as nausea and vomiting, you will be given other medicines before treatment with trabectedina and whenever you need them during treatment.

You will receive an infusion every 3 weeks, although occasionally your doctor may recommend delaying the dose so that you receive the most suitable dose of trabectedina.

The total duration of treatment will depend on your progress and how you feel. Your doctor will tell you how long your treatment can last. If you have any further questions about the use of this medicine, ask your doctor.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medicine and the amount ingested.

4. Possible side effects

Like all medicines, this medicine or its combination with PLD can cause side effects, although not everyone gets them.

If you are not sure what the following effects are, ask your doctor to explain them in more detail.

Severe side effects caused by treatment with Trabectedina EVER Pharma:

Very common: may affect more than 1 in 10 people

• You may have elevated levels of the yellow pigment bilirubin in the blood, which can cause jaundice (yellowing of the skin, mucous membranes, and eyes).

• Your doctor will regularly ask for blood tests to detect any abnormalities in the blood.

Common: may affect up to 1 in 10 people

• You may have blood infections (septicemia) if your immune system is severely affected. If you have a fever, go to your doctor immediately.

• You may also experience muscle pain (myalgia). You may also suffer nerve damage, which can cause muscle pain, weakness, and numbness. You may experience swelling or swelling of the extremities and a tingling sensation on the skin.

• You may have a reaction at the injection site. The trabectedina infusion may leak out of the vein during administration and cause damage and destruction of the cells of the tissues near the injection site (tissue necrosis; see also section 2 "Warnings and precautions"), which may require surgical intervention.

• You may have an allergic reaction. In this case, you may experience fever, difficulty breathing, redness or rash, feeling of dizziness (nausea) or feeling of discomfort (vomiting).

• When trabectedina is used in combination with PLD, you may experience fainting or fainting. You may also notice that your heart beats too hard or too fast (palpitations), suffer from weakness in the ventricles, which are the main pumping chambers of the heart (left ventricular dysfunction), or have a sudden blockage of a pulmonary artery (pulmonary embolism).

Uncommon: may affect up to 1 in 100 people

• You may experience severe muscle pain and pain, stiffness, and muscle weakness. You may also experience darkening of the urine color. All of the above could be a sign of muscle damage (rhabdomyolysis).

• Your doctor may ask for blood tests in certain situations to prevent muscle damage (rhabdomyolysis). In some very severe cases, this muscle damage could lead to kidney failure. If you experience severe muscle pain or weakness, go to your doctor immediately.

• You may experience difficulty breathing, irregular heartbeat, decreased urine output, sudden changes in mental status, mottled skin, very low blood pressure associated with abnormal laboratory results (decreased platelet count). If you experience any of these symptoms or signs, go to your doctor immediately.

Reporting of side effects

If you experience any side effects, talk to your doctor, even if they are not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Trabectedina 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 on the label of the vial after EXP. The expiry date refers to the last day of the month stated.

Store in a refrigerator (2 °C-8 °C).

Information on the stability of the reconstituted and diluted solutions is included in the section for healthcare professionals.

Do not use this medicine if you notice visible particles after reconstitution or dilution of the medicine.

Disposal of unused medicine and all materials that have come into contact with it should be done according to local regulations for cytotoxic medicines.

6. Package Contents and Additional Information

Composition of Trabectedina EVER Pharma

• The active substance is trabectedin.

Trabectedina EVER Pharma 0.25 mg: each vial of powder contains 0.25 mg of trabectedin

Trabectedina EVER Pharma 1 mg: each vial of powder contains 1 mg of trabectedin.

• The other ingredients are citric acid (E330), arginine, phosphoric acid concentrated (for pH adjustment) (E338), and sodium hydroxide (for pH adjustment) (E524).

Appearance and Package Contents of the Product

Trabectedina EVER Pharma is a powder for concentrate for solution for infusion. The powder is white or off-white and is presented in a glass vial.

The 0.25 mg trabectedin glass vial is closed with a rubber stopper sealed with a light blue aluminum flip-off cap.

The 1 mg trabectedin glass vial is closed with a rubber stopper sealed with a pink aluminum flip-off cap.

Each package contains 1 vial of 0.25 mg or 1 mg of trabectedin.

Marketing Authorization Holder

EVER Valinject GmbH

Oberburgau 3

4866 Unterach am Attersee

Austria

Manufacturer

EVER Pharma Jena GmbH

Otto-Schott-Str. 15

07745 Jena

Germany

EVER Pharma Jena GmbH

Brüsseler Str. 18

07747 Jena

Germany

Local Representative

EVER Pharma Therapeutics Spain, S.L.

C/Toledo 170

28005 Madrid

Spain

This medicine is authorized in the Member States of the European Economic Area, with the following names:

Date of last revision of this leaflet: 04/24

Other sources of information

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

This information is intended only for healthcare professionals:

Instructions for use, preparation, handling, and disposal

Proper procedures should be followed for the proper handling and disposal of cytotoxic medicines. Disposal of unused medicine and all materials that have come into contact with it should be done according to local regulations for cytotoxic medicines.

The healthcare professional should have received training in the correct techniques for reconstitution and dilution of Trabectedina EVER Pharma or its combination with DLP, and during reconstitution and dilution of the drug, should wear protective clothing, including a mask, protective glasses, and gloves. If you are pregnant, you should not work with this medicine.

Preparation for intravenous infusion

Trabectedina EVER Pharma should be reconstituted and then diluted before infusion (see also section 3). Proper aseptic techniques should be used.

Trabectedina EVER Pharma should not be administered mixed with other medicines that are not the diluent, in the same infusion. No incompatibilities have been observed between Trabectedina EVER Pharma and type I glass vials, or with polyvinyl chloride (PVC) and polyethylene (PE) bags and tubes, or with polyisoprene reservoirs or implantable titanium vascular access systems.

When Trabectedina EVER Pharma is used in combination with DLP, the intravenous line should be flushed well with 50 mg/ml (5%) glucose solution for infusion after administration of DLP and before administration of Trabectedina EVER Pharma. The use of a diluent other than 50 mg/ml (5%) glucose solution for infusion may cause precipitation of DLP. (See also the summary of product characteristics of DLP, which contains specific instructions for its handling.)

Reconstitution instructions

Trabectedina EVER Pharma 0.25 mg:inject 5 ml of sterile water for injectable preparations into the vial.

Trabectedina EVER Pharma 1 mg:inject 20 ml of sterile water for injectable preparations into the vial.

A syringe should be used to inject the correct amount of sterile water for injectable preparations into the vial. Shake the vial until the drug is completely dissolved. The reconstituted solution is clear, colorless, or slightly yellowish, without visible particles.

The reconstituted solution has a concentration of 0.05 mg/ml of trabectedin. It requires further dilution and is intended for single use.

Dilution instructions

Dilute the reconstituted solution with a 9 mg/ml (0.9%) sodium chloride solution for infusion or a 50 mg/ml (5%) glucose solution for infusion. Calculate the volume needed as follows:

Volume (ml) = BSA (m2) x individual dose (mg/m2)

0.05 mg/ml

BSA = body surface area

The appropriate amount of reconstituted solution should be withdrawn from the vial; if intravenous administration is to be performed through a central venous line, add the reconstituted solution to an infusion bag containing ≥ 50 ml of diluent (9 mg/ml (0.9%) sodium chloride solution for infusion or 50 mg/ml (5%) glucose solution for infusion), with the concentration of trabectedin in the infusion solution being ≤ 0.030 mg/ml.

If a central venous line cannot be used and a peripheral venous line must be used, the reconstituted solution should be added to an infusion bag containing ≥ 1,000 ml of diluent (9 mg/ml (0.9%) sodium chloride solution for infusion or 50 mg/ml (5%) glucose solution for infusion).

Before intravenous administration, a visual inspection of the parenteral solutions should be performed to detect the possible presence of particles. The prepared infusion solution should be administered immediately.

Stability of the solutions during use

Reconstituted solution

After reconstitution, chemical and physical stability has been demonstrated for 30 hours up to 25 °C.

From a microbiological point of view, the reconstituted solution should be diluted and used immediately. If it is not diluted and used immediately, the useful storage times and conditions before use of the reconstituted solution will be the responsibility of the user and should normally not exceed 24 hours at 2 °C-8 °C, unless the reconstitution has been performed under validated and controlled aseptic conditions.

Diluted solution

After dilution, chemical and physical stability has been demonstrated for 30 hours up to 25 °C.