TRABECTEDINE TEVA 0.25 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Leaflet:information for the patient

Trabectedina Teva 0.25 mg powder for concentrate for solution for infusion EFG

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

Read the entire leaflet carefully before starting to use this medication,as 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.
• If you experience side effects, consult your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the leaflet

1. What is Trabectedina Teva and what is it used for
2. What you need to know before starting to use Trabectedina Teva
3. How to use Trabectedina Teva
4. Possible side effects

5 Conservation of Trabectedina Teva

1. Package contents and additional information

1. What is Trabectedina Teva and what is it used for

This medication has trabectedina as its active ingredient. This medication is an anticancer medication that works by preventing the multiplication of tumor cells.

This medication is used for the treatment of patients with advanced soft tissue sarcoma, when previous treatment with other medications has not been effective or when patients cannot use other medications. Soft tissue sarcoma is a malignant neoplasm that originates in some part of the soft tissues, such as muscles, fat, or other tissues (e.g., cartilage or blood vessels).

This medication, in combination with liposomal pegylated doxorubicin (DLP, another antitumor medication), is used in the treatment of patients with ovarian cancer who have suffered a relapse after at least 1 previous treatment and who are not resistant to anticancer medications that contain platinum compounds.

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

Do not use Trabectedina Teva

• if you are allergic to trabectedina or to 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 this medication.

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

Consult 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.
• 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 may produce side effects that affect the blood and liver.
• If, despite taking anti-emetic 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 general 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 Teva

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 that contains live virus particles. The use of medications that contain phenytoin (for the treatment of epilepsy) is not recommended with trabectedina, as the effect of phenytoin may be reduced.

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:

• reduced (e.g., using medications that contain 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., medications that contain 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 that contain statins (to reduce cholesterol levels and prevent cardiovascular disease) are an example of medications that can cause muscle damage.

Use ofTrabectedina Teva withalcohol

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 for up to 3 months after completing 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, 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 weak during treatment with trabectedina. Do not drive or use tools or machines if you experience any of these side effects.

Trabectedina Teva contains potassium

This medication contains 1.28 mmol (or 50.22 mg) of potassium per 2.7 mg of trabectedina, which should be taken into account in patients with renal insufficiency or in patients with low-potassium diets.

3. How to use Trabectedina Teva

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 specialized healthcare professionals 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 should 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 medications 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 other questions about the use of this medication, ask your doctor.

4. Possible side effects

Like all medications, this medication or its combination with DLP may 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.

Serious 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 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 the doctor immediately.

• You may also feel muscle pain (myalgia). You may also suffer nerve damage, which causes muscle pain, weakness, and numbness. You may experience swelling of the body or limbs 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 DLP, you may experience syncope or fainting. Additionally, you may 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 feel 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 general 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 your 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 damage and death of the tissue cells 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. Blisters, peeling, and darkening of the skin may appear in the area. 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 serious side effects:

Very common: may affect more than 1 in 10 people

• You may:
• • feel tired
  • have difficulty breathing and coughing
  • notice back pain
  • have excess fluid in the body (edema)
  • develop bruises (hematomas) more easily
  • have 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-emetic medications, you experience nausea, vomiting, or are unable to drink liquids and, therefore, urinate less, go to the doctor immediately.

• You may have a headache.

• You may suffer from 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 who receive 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 who receive 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 Pharmacovigilance System for Human Use Medicines: 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 Teva

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 indicated.

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 Teva

• The active substance is trabectedina.
• 1. Trabectedina 0.25 mg: each vial of powder contains 0.25 mg of trabectedina.
  2. Trabectedina 1 mg: each vial of powder contains 1 mg of trabectedina.
• The other ingredients are hydrochloride of L-arginine, phosphoric acid (for pH adjustment) and potassium hydroxide (for pH adjustment).

Appearance and Package Contents of the Product

Trabectedina Teva 0.25 mg

Trabectedina Teva is a powder for concentrate for solution for infusion. The powder is white to off-white and is presented in a colourless glass vial with a bromobutyl rubber stopper sealed with a flip-off type aluminium cap with a blue-green polypropylene disc.

Trabectedina Teva 1 mg

Trabectedina Teva is a powder for concentrate for solution for infusion. The powder is white to off-white and is presented in a colourless glass vial with a bromobutyl rubber stopper sealed with a flip-off type aluminium cap with a pink polypropylene disc.

The vials may be enclosed in a protective sleeve (a transparent, colourless protective film covering the vial) to provide additional safety measures.

Each pack contains 1 vial of 0.25 mg or 1 vial of 1 mg of trabectedina.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Teva B.V.

Swensweg, 5

2031GA Haarlem

Netherlands

Manufacturer

PLIVA Hrvatska d.o.o. (PLIVA Croatia Ltd.)

Prilaz baruna Filipovica 25

10000, Zagreb

Croatia

or

S.C. Sindan-Pharma S.R.L.

11 Ion Mihalache Ave., the 1st district

Bucharest

011171

Romania

You can request more information about this medicine by contacting the local representative of the Marketing Authorisation Holder:

Teva Pharma, S.L.U.

C/ Anabel Segura, 11

Edificio Albatros B, 1ª planta

28108 Alcobendas (Madrid) Spain

Date of the last revision of this leaflet:January 2021

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

The correct 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 in accordance with local regulations for cytotoxic medicines.

The healthcare professional should have received training in the correct techniques for reconstitution and dilution of trabectedina or its combination with DLP, and during the reconstitution and dilution of the medicine, 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 should be reconstituted and then diluted before infusion (see also section 3). Aseptic techniques should be used.

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

When trabectedina 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. 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 summary of product characteristics of DLP, which contains specific instructions for its handling.)

Reconstitution Instructions

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

Trabectedina 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 medicine is completely dissolved. The reconstituted solution is clear, colourless or slightly yellowish, without visible particles.

The reconstituted solution has a concentration of 0.05 mg/ml of trabectedina. 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 required volume as follows:

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

0.05 mg/ml

SC = body surface area

Extract the appropriate amount of reconstituted solution 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 a trabectedina concentration in the infusion solution ≤ 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 in-use storage times and conditions prior to use of the reconstituted solution are the responsibility of the user and normally should not be greater than 24 hours at 2°C-8°C, unless the reconstitution has been performed in validated and controlled aseptic conditions.

Diluted Solution

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

From a microbiological point of view, the diluted solution should be used immediately. If it is not used immediately, the in-use storage times and conditions prior to use of the diluted solution are the responsibility of the user and normally should not be greater than 24 hours at 2°C-8°C, unless the dilution has been performed in validated and controlled aseptic conditions.