YONDELIS 1 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Yondelis 0.25 mg powder for concentrate for solution for infusion.

Yondelis 1 mg powder for concentrate for solution for infusion.trabectedin

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 side effects, consult your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the package leaflet

1. What is Yondelis and what is it used for
2. What you need to know before you use Yondelis

1. How to use Yondelis
2. Possible side effects

1. Storage of Yondelis
2. Contents of the pack and further information

1. What is Yondelis and what is it used for

Yondelis contains the active substance trabectedin. Yondelis is an anticancer medicine that works by preventing the multiplication of tumor cells.

Yondelis 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 the soft tissues, such as muscles, fat, or other tissues (e.g., cartilage or blood vessels).

Yondelis 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 use Yondelis

Do not use Yondelis

• if you are allergic to trabectedin 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

Consult your doctor before starting treatment with Yondelis.

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

Consult your doctor before starting treatment with Yondelis 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.

Seek medical attention immediately if you experience any of the following:

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

• If you experience nausea, vomiting, or are unable to drink fluids and therefore urinate less, despite taking anti-emetic medication, seek medical attention 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 Yondelis infusion is leaking out of the vein during administration. This could damage or destroy the cells of the surrounding tissues (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 nausea or 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

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

Other medicines and Yondelis

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

You should not use Yondelis 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 Yondelis is not recommended, as the effect of phenytoin may be reduced.

If you use any of the following medicines during treatment with Yondelis, you need to be closely monitored, as the effects of Yondelis 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 (immunosuppressant), or verapamil (for hypertension and other heart disorders)).

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

If, at the same time as Yondelis or the combination of Yondelis and PLD, you are being administered 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 Yondelis with alcohol

Alcohol consumption should be avoided during treatment with Yondelis, as it can damage the liver.

Pregnancy, breastfeeding, and fertility

Pregnancy

Yondelis 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 Yondelis 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 Yondelis may cause genetic damage to the fetus.

Breastfeeding

Yondelis 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 Yondelis and for up to 5 months after treatment.

Because there is a risk that treatment with Yondelis 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 experience loss of strength during treatment with Yondelis. Do not drive or use tools or machines if you experience any of these side effects.

Yondelis contains potassium

This medicine contains potassium, less than 1 mmol (39 mg) per vial; this is essentially "potassium-free".

3. How to use Yondelis

Yondelis 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 Yondelis 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, Yondelis should be reconstituted and diluted for intravenous use. Each time you receive Yondelis for the treatment of soft tissue sarcoma, it will take approximately 24 hours for the entire solution to be administered. The treatment of ovarian cancer will last 3 hours.

In order to avoid irritation at the injection site, it is recommended that Yondelis 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 Yondelis 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 Yondelis.

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.

4. Possible side effects

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

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

Serious side effects caused by treatment with Yondelis:

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, seek medical attention 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 of the body or limbs and a tingling sensation on the skin.

• You may have a reaction at the injection site. The Yondelis infusion may leak out of the vein during administration and cause damage and destruction of the cells of the surrounding tissues (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 nausea or discomfort (vomiting).

• When Yondelis is used 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 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 weakness, 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 severe cases, this muscle damage could lead to kidney failure. If you experience severe muscle pain or weakness, seek medical attention 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, seek medical attention immediately.

• You may experience abnormal fluid accumulation in the lungs, which can cause 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, seek medical attention immediately.

• You may notice that the Yondelis infusion leaks out of the vein while 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 cell 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 tissue damage to become visible. If you experience any of these symptoms or signs, seek medical attention 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, seek medical attention 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 and joint 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, seek medical attention 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 medication, you experience nausea, vomiting, or are unable to drink fluids and therefore urinate less, seek medical attention immediately.

• You may experience headache and sleep disturbances.

• 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 Yondelis is used with PLD.

• Patients receiving Yondelis 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 blistering 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 flashes or skin rash.

• Patients receiving Yondelis with PLD for ovarian cancer may experience increased skin pigmentation.

Reporting of 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 national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Yondelis

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 is the last day of the month shown.

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 in accordance with local regulations for cytotoxic medicines.

6. Container contents and additional information

Yondelis composition

• The active ingredient is trabectedin.

Yondelis 0.25 mg: each vial of powder contains 0.25 mg of trabectedin

Yondelis 1 mg: each vial of powder contains 1 mg of trabectedin.

• The other components are sucrose, potassium dihydrogen phosphate, phosphoric acid (for pH adjustment) and potassium hydroxide (for pH adjustment).

Product appearance and container contents

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

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

Marketing authorization holder and manufacturer

Pharma Mar, S.A.

Avda. de los Reyes 1

Polígono Industrial La Mina

28770 Colmenar Viejo (Madrid)

Spain

Tel: +34 91 846 60 00

Fax: +34 91 846 60 01

Further information on this medicinal product can be obtained from the marketing authorization holder.

Date of last revision of this leaflet:

Other sources of information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.

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 medicinal products. Disposal of unused medicinal product and all materials that have come into contact with it should be carried out in accordance with local regulations for cytotoxic medicinal products.

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

Preparation for intravenous infusion

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

Appropriate aseptic techniques should be used.

Yondelis should not be administered mixed with other medicinal products, except for the diluent, in the same infusion. No incompatibilities have been observed between Yondelis 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 Yondelis 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 Yondelis. 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

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

Yondelis 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 medicinal product 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 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 trabectedin 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 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 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 in validated and controlled aseptic conditions.

Diluted solution

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