TRABECTEDINE SUN 0.25 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

2. What you need to know before starting to use Trabectedina Sun

Do not use Trabectedina Sun

• if you are allergic to trabectedina or any of the other components of this medication (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

Consult your doctor before starting to use trabectedina.

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

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

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

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

• If you have a fever, as trabectedina can produce side effects that affect the blood and liver.
• If, despite taking anti-nausea medications, you experience nausea, vomiting, or are unable to drink liquids and, therefore, urinate less, go to the doctor immediately.
• If you notice intense 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 have 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 generalized 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 medications and Trabectedina Sun

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

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 medications containing phenytoin (for epilepsy treatment) is not recommended with trabectedina, as the effect of phenytoin may decrease.

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

• decreased (e.g., using medications containing rifampicin (for bacterial infections), phenobarbital (for epilepsy), or St. John's Wort (Hypericum perforatum, a medicinal plant used for depression treatment)) or
• increased (e.g., medications 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 immune system), or verapamil (for hypertension and other heart disorders)).

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

If, in addition to trabectedina or the combination of trabectedina and DLP, you are receiving another medication that can cause liver or muscle damage (rhabdomyolysis), you may be closely monitored, as the risk of liver or muscle damage may increase. Medications containing statins (to reduce cholesterol levels and prevent cardiovascular diseases) are an example of medications that can cause muscle damage.

Use of Trabectedina Sun with alcohol

Alcohol consumption should be avoided during treatment with trabectedina, as it can 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 medication.

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

If you become pregnant, you should tell 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 must stop breastfeeding and not resume it until your doctor confirms it is safe to do so.

Fertility

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

Because there is a risk that treatment with trabectedina may cause irreversible infertility, it is recommended that patients seek advice on the possibility of preserving their eggs or sperm before treatment.

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

Driving and using machines

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

Trabectedina Sun contains potassium

This medication contains potassium, less than 1 mmol (39 mg) per vial, i.e., it is essentially "potassium-free).

3. How to use Trabectedina Sun

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 medications.

For the treatment of soft tissue sarcoma, the normal dose is 1.5 mg/m2 of body surface area. During the treatment period, your doctor will closely monitor you and decide what the most suitable dose of trabectedina is 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 DLP.

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 discomfort (nausea) and vomiting, you will be given other medications before treatment with trabectedina and whenever needed 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 medication, ask your doctor.

4. Possible side effects

Like all medications, this medication or its combination with DLP can cause side effects, although not everyone will experience them.

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

Severe side effects caused by treatment with trabectedina:

Very common: may affect more than 1 in 10 people

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

• Your doctor will regularly request blood tests to detect any blood abnormalities.

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 the doctor immediately.

• You may also experience muscle pain (myalgia). You may also suffer nerve damage, which causes muscle pain, weakness, and numbness. You may experience generalized or partial swelling and a tingling sensation in 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 DLP, you may experience syncope or fainting. Additionally, you may notice that your heart is beating 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 intense 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 request 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 intense muscle pain or weakness, go to the 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 the doctor immediately.

• You may have an abnormal accumulation of fluid in the lungs, which causes swelling (pulmonary edema).

• You may notice generalized 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. If this happens, go to the doctor immediately.

• You may notice that the trabectedina infusion is leaking out of the vein while it is being administered (extravasation). Therefore, you may notice redness, swelling, itching, and discomfort at the injection site. If you experience any of these symptoms or signs, tell your doctor or nurse immediately.

This could lead to tissue damage and death around the injection site (tissue necrosis), which may require surgery.

Some of the symptoms or signs of extravasation may not be visible until several hours after it occurs. In the area, blisters, peeling, and darkening of the skin may appear. It may take a few days for the extent of tissue damage to become visible. If you experience any of these symptoms or signs, go to the doctor immediately.

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

• You may experience yellowing of the skin and eyes (jaundice), pain in the upper right abdomen, nausea, vomiting, general feeling of discomfort, difficulty concentrating, disorientation, or confusion, drowsiness. These signs may indicate that the liver is not functioning normally. If you experience any of these symptoms or signs, go to the doctor immediately.

Other less severe side effects:

Very common: may affect more than 1 in 10 people

• You may:
• • feel tired
  • experience difficulty breathing and coughing
  • notice back pain
  • have excess fluid in the body (edema)
  • develop bruises (hematomas) more easily
  • experience nosebleeds
  • be more prone to infections. An infection can also cause fever.

If you experience any of these symptoms, go to the doctor immediately.

• You may also experience some digestive symptoms such as decreased appetite, nausea, or vomiting, abdominal pain, diarrhea, or constipation. If, despite taking anti-nausea medications, you experience nausea, vomiting, or are unable to drink liquids and, therefore, urinate less, go to the doctor immediately.

• You may experience headaches.

• You may experience mucosal inflammation, which appears as redness and swelling of the inside of the mouth, causing painful ulcers and sores (stomatitis), or as inflammation of the gastrointestinal tract, when trabectedina is used in combination with DLP.

• Patients receiving trabectedina in combination with DLP for ovarian cancer may also experience hand-foot syndrome. It appears as redness of the skin on the palms of the hands, fingers, and soles of the feet, which can swell and turn purple over time. The lesions can be dry and scaly or appear as blisters with ulcers.

Common: may affect up to 1 in 10 people

• You may experience fluid loss, weight loss, digestive discomfort, and altered sense of taste.

• You may lose hair (alopecia).

• You may also experience dizziness, low blood pressure, and hot flashes or skin rash.

• Patients receiving trabectedina in combination with DLP for ovarian cancer may experience increased skin pigmentation.

• You may notice joint pain.

• You may experience sleep disturbances.

Reporting side effects

If you experience any side effects, consult your doctor, even if they are not listed in this leaflet. You can also report them directly through the Spanish Medication Surveillance System for Human Use: http://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

5. Storage of Trabectedina Sun

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 CAD or EXP. The expiry date refers to the last day of the month stated.

Store in a refrigerator (between 2°C and 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 in accordance with local regulations for cytotoxic medicines.

6. Package Contents and Additional Information

Composition of Trabectedina Sun

• The active substance is trabectedin.
• 1. Trabectedina Sun 0.25 mg: each vial of powder contains 0.25 mg of trabectedin.
  2. Trabectedina Sun 1 mg: each vial of powder contains 1 mg of trabectedin.
• The other ingredients are sucrose, potassium dihydrogen phosphate, phosphoric acid (for pH adjustment), and potassium hydroxide (for pH adjustment).

Appearance and Package Contents of the Product

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

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

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Sun Pharmaceutical Industries Europe B.V.,

Polarisavenue 87

2132JH Hoofddorp

Netherlands

Manufacturer

Sun Pharmaceutical Industries Europe B.V.,

Polarisavenue 87

2132JH Hoofddorp

Netherlands

O

Terapia S.A.

Str. Fabricii nr. 124

400632, Cluj-Napoca

Romania

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

Sun Pharma Laboratories, S.L.

Rambla de Catalunya, 53-55

08007 – Barcelona

Spain

Tel.: +34 93 342 78 90

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

Germany Trabectedin SUN 0.25 mg Powder for concentrate for solution for infusion

Trabectedin SUN 1 mg Powder for concentrate for solution for infusion

Austria Trabectedin SUN 0.25 mg Powder for concentrate for solution for infusion

Trabectedin SUN 1 mg Powder for concentrate for solution for infusion

Belgium Trabectedine SUN 0.25 mg powder for concentrate for solution for infusion

Trabectedine SUN 1 mg powder for concentrate for solution for infusion

Denmark Trabectedin SUN

France TRABECTEDINE SUN 0.25 mg, powder for solution to be diluted for infusion

TRABECTEDINE SUN 1 mg, powder for solution to be diluted for infusion

Italy Trabectedina SUN

Spain Trabectedina SUN 0.25 mg powder for concentrate for solution for infusion EFG

Trabectedina SUN 1 mg powder for concentrate for solution for infusion EFG

Sweden Trabektedin SUN 0.25 mg powder for concentrate for infusion solution

Trabektedin SUN 1 mg powder for concentrate for infusion solution

Date of the last revision of this leaflet:October 2022

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/)

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This information is intended only for healthcare professionals:

Instructions for use, preparation, handling, and disposal

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

The healthcare professional should have received training in the correct techniques for reconstitution and dilution of trabectedin or its combination with DLP, and during reconstitution and dilution of the drug, should wear protective clothing, including a mask, protective glasses, and gloves. Accidental contact with the skin, eyes, or mucous membranes should be treated immediately with plenty of water. If you are pregnant, you should not work with this medicine.

Preparation for intravenous infusion

Trabectedina Sun should be reconstituted and then diluted before infusion (see also section 3).

Proper aseptic techniques should be used.

Trabectedina Sun should not be administered mixed with other medicines that are not the diluent in the same infusion. No incompatibilities have been observed between trabectedin 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 trabectedin 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 trabectedin. The use of a diluent other than 50 mg/ml (5%) glucose solution for infusion may cause precipitation of DLP. (See also section 4.2 and the DLP summary of product characteristics, which contains specific instructions for its handling.)

Reconstitution instructions

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

Trabectedina Sun 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 any 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 normally should 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.