TRABECTEDINE TEVA 1 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package 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 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 pack

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

5 Conservation of Trabectedina Teva

1. Contents of the pack and further information

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

This medicinal product contains the active substance trabectedin. This medicinal product is an anticancer medicine that works by preventing the multiplication of tumour cells.

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

This medicinal product 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 anticancer medicines that contain platinum compounds.

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

Do not use Trabectedina Teva

• if you are allergic to trabectedin or any of the other ingredients of this medicinal product (listed in section 6);
• if you have a severe infection;
• if you are breast-feeding;
• if you are going to receive the yellow fever vaccine.

Warnings and precautions

Talk to your doctor before you start using this medicinal product.

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

Talk to your doctor before you start treatment with trabectedin 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 your doctor immediately if you experience any of the following:

• If you have a fever, as trabectedin may cause side effects that affect the blood and liver.
• If, despite taking anti-emetic medicines, you experience nausea, vomiting or are unable to drink liquids and therefore urinate less, go to your doctor immediately.
• If you notice severe muscle pain or weakness, as this could be a sign of muscle damage (rhabdomyolysis, see section 4).
• If you notice that the trabectedin 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 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, and requires urgent clinical evaluation by your doctor.

Children and adolescents

Trabectedin should not be used in children under 18 years of age with paediatric sarcomas.

Other medicines and Trabectedina Teva

Tell your doctor if you are using, have recently used or might use any other medicines.

You should not use trabectedin 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 medicines that contain phenytoin (for the treatment of epilepsy) is not recommended with trabectedin, as the effect of phenytoin may be reduced.

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

• reduced (e.g. using medicines 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. medicines that contain ketoconazole or fluconazole (for fungal infections), ritonavir (for HIV infection), clarithromycin (for bacterial infections), aprepitant (to prevent nausea and vomiting), cyclosporin (to suppress the immune system) or verapamil (for hypertension and other heart disorders)).

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

If, at the same time as trabectedin or the combination of trabectedin and PLD, you are being given another medicine that can cause liver or muscle damage (rhabdomyolysis), you may be closely monitored as the risk of liver or muscle damage may be increased. Medicines that contain statins (to reduce cholesterol levels and prevent cardiovascular disease) are an example of medicines that can cause muscle damage.

Use ofTrabectedina Teva withalcohol

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

Pregnancy, breast-feedingand fertility

Pregnancy

Trabectedin should not be used during pregnancy. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine.

Women of childbearing potential must use effective contraceptive methods during treatment with trabectedin and for up to 3 months after finishing treatment.

If you become pregnant, you should inform your doctor immediately; you are also advised to receive genetic counselling, as trabectedin may cause genetic damage to the foetus.

Breast-feeding

Trabectedin should not be administered to patients who are breast-feeding. Therefore, you must stop breast-feeding before starting treatment and not restart until your doctor confirms that it is safe to do so.

Fertility

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

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

Genetic counselling 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 trabectedin. Do not drive or use tools or machines if you experience any of these side effects.

Trabectedina Teva contains potassium

This medicinal product contains 1.28 mmol (or 50.22 mg) of potassium per 2.7 mg of trabectedin, which should be taken into account in patients with renal impairment or in patients on a low-potassium diet.

3. How to use Trabectedina Teva

Trabectedin should be administered under the supervision of a doctor with experience in the use of chemotherapy. Its use should be restricted to qualified oncologists and other healthcare professionals specialised in the administration of cytotoxic medicinal products.

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

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

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

In order to avoid irritation at the injection site, it is recommended that trabectedin 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 trabectedin and whenever you need them during treatment.

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

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 on the use of this medicinal product, ask your doctor.

4. Possible side effects

Like all medicines, this medicinal product or its combination with PLD can cause side effects, although not everybody gets them.

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

Serious side effects caused by treatment with trabectedin:

Very common: may affect more than 1 in 10 people

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

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

Common: may affect up to 1 in 10 people

• You may have blood infections (septicaemia) 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 experience nerve damage, which causes muscle pain, weakness and numbness. You may experience general or partial swelling and a sensation of tingling in the skin.

• You may have a reaction at the injection site. The trabectedin infusion may leak out of the vein during administration and cause injury 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 trabectedin is used in combination with PLD, you may experience fainting or syncope. You may also notice that your heart beats too fast or too hard (palpitations), suffer from weakness in the ventricles, which are the main pumping chambers of the heart (left ventricular dysfunction) or 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 colour of the urine. All of the above could be a sign of muscle damage (rhabdomyolysis).

• Your doctor may ask you for blood tests in certain situations, in order to prevent muscle damage (rhabdomyolysis). In some 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.

• You may experience abnormal fluid accumulation in the lungs, which causes swelling (pulmonary oedema).

• 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 your doctor immediately.

• You may notice that the trabectedin 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. Blisters, peeling and darkening of the skin may appear in the area. It may take a few days for the extent of the tissue damage to become visible. If you experience any of these symptoms or signs, go to your 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 your doctor immediately.

Other less serious 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 (haematoma) more easily
  • experience nosebleeds
  • be more prone to infections. An infection can also cause fever.

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

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

• You may experience headache.

• 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 trabectedin is used in combination with PLD.

• Patients who receive trabectedin in combination with PLD for ovarian cancer may also experience hand-foot syndrome. This 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 ulceration.

Common: may affect up to 1 in 10 people

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

• You may lose hair (alopecia).

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

• Patients who receive trabectedin in combination with PLD for ovarian cancer may experience increased skin pigmentation.

• You may experience joint pain.

• You may experience sleep disturbances.

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 side effects directly via the Spanish Medicines Monitoring System for Human Use: http://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicinal product.

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 colorless glass vial with a bromobutyl rubber stopper sealed with a flip-off type aluminum cap with a blue-green colored 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 colorless glass vial with a bromobutyl rubber stopper sealed with a flip-off type aluminum cap with a pink colored polypropylene disc.

The vials may be enclosed in a protective sleeve (a transparent, colorless 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 Authorization Holder and Manufacturer

Marketing Authorization 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 authorization 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 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 should be reconstituted and then diluted before infusion (see also section 3). Appropriate 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 well flushed 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 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 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) = BSA (m2) x individual dose (mg/m2)

0.05 mg/ml

BSA = body surface area

Withdraw 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 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 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 useful storage times and conditions before use of the diluted solution will be the responsibility of the user and normally should not exceed 24 hours at 2°C-8°C, unless the dilution has been performed in validated and controlled aseptic conditions.