Patient Information Leaflet

Yondelis 0.25 mg powder for concentrate for solution for infusion.

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

Read this leaflet carefully before you start using this medicine, because 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 any side effects, consult your doctor, even if they are not listed in this leaflet. See section 4.

1. How to use Yondelis
2. Possible side effects

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

Yondelis contains trabectedin as its active ingredient. Yondelis is an anticancer medication that works by preventing the multiplication of cancer cells.

Yondelis is used to treat patients with advanced soft tissue sarcoma, when previous treatment with other medications has been ineffective or when patients cannot use other medications. Soft tissue sarcoma is a malignant neoplasm that begins in some soft tissues, such as muscles, fat, or other tissues (for example, cartilage or blood vessels).

Yondelis in combination with pegylated liposomal doxorubicin (DLP, another antitumoral medication) is used to treat patients with ovarian cancer who have experienced a recurrence after at least 1 previous treatment and who are not resistant to anticancer medications containing platinum compounds.

No 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 to be given the yellow fever vaccine.

Warnings and precautions

Consult your doctor before starting to use Yondelis.

You must not use Yondelis or its combination with DLP 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.

• received high doses of anthracyclines in the past.

Seek medical attention immediately if any of the following occur:

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

• if, despite taking anti-vomiting medication, you experience nausea, vomiting, or are unable to drink liquids and, therefore, urinate less, seek medical attention immediately.

• if you experience intense 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 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 flushing of the skin, or rash, dizziness, or nausea, or vomiting (see section 4).

• if you experience 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 may cause an excessive accumulation of fluid in your tissues, and requires urgent clinical evaluation by your doctor.

Children and adolescents

Yondelis must not be used in children under 18 years with pediatric sarcomas.

Other medicines and Yondelis

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

You must not use Yondelis if you are to be vaccinated against yellow fever and it is not recommended to use Yondelis if you are to be given a vaccine that contains live virus particles. It is not recommended to use medicines that contain phenytoin (for epilepsy treatment) with Yondelis, as the effect of phenytoin may be reduced.

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

• reduced (for example, using medicines that contain rifampicin (for bacterial infections), phenobarbital (for epilepsy), or St. John's Wort (Hypericum perforatum, a medicinal plant used for depression treatment)) or

• increased (for example, medicines that contain ketoconazole or fluconazole (for fungal infections), ritonavir (for HIV infection), clarithromycin (for bacterial infections), aprepitant (to prevent nausea and vomiting), cyclosporin (inhibit the body's defense system), or verapamil (for hypertension and other heart problems)).

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

If, in addition to Yondelis or the combination of Yondelis and DLP, you are being given another medicine that can cause liver or muscle damage (rhabdomyolysis), you may be closely monitored, as this could increase the risk of liver or muscle damage. Medicines that contain statins (to reduce cholesterol levels and prevent cardiovascular diseases) are an example of medicines that can cause muscle damage.

Use of Yondelis with alcohol

You must avoid consuming alcohol during treatment with Yondelis, as it can damage the liver.

Pregnancy, breastfeeding, and fertility

Pregnancy

You must not use Yondelis during pregnancy. If you are pregnant, think you may be pregnant, or intend to become pregnant, consult your doctor before using this medicine.

Women of childbearing age must use effective contraceptive methods during treatment with Yondelis and for 3 months after treatment is completed.

If you become pregnant, inform your doctor immediately; in addition, it is recommended that you receive genetic counseling, as Yondelis may cause genetic damage to the fetus.

Breastfeeding

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

Fertility

Men of childbearing age must use effective contraceptive methods during treatment with Yondelis and for 5 months after treatment is completed.

Due to the risk of 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 patients who wish to have children after treatment.

Driving and operating machinery

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

Yondelis contains potassium

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

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 specialized healthcare professionals in the administration of cytotoxic drugs.

The usual dose for the treatment of soft tissue sarcoma is 1.5 mg/m² of body surface area. During treatment, your doctor will closely monitor you and decide on the most suitable dose of Yondelis 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.

The usual dose for the treatment of ovarian cancer is 1.1 mg/m² of body surface area after administration of 30 mg/m² of body surface area of DLP.

Before administration, Yondelis must 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 enter your bloodstream. Treatment of ovarian cancer will last 3 hours.

To avoid irritation in the injection area, it is recommended that Yondelis be administered through a central venous line.

To protect the liver and reduce the risk of adverse effects such as nausea and vomiting, you will be given other medications before treatment with Yondelis and as needed during treatment.

You will receive a perfusion 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 may last. If you have any other questions about the use of this medication, ask your doctor.

Like all medicines, this medicine or its combination with DLP may cause side effects, although not everyone will experience them.

If you are unsure about what the following list of side effects are, ask your doctor to explain them in more detail.

Severe side effects caused by treatment with Yondelis:

Very common: may affect more than 1 in 10 people

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

• Your doctor will ask you to have regular blood tests to detect any abnormalities in your blood.

Common: may affect up to 1 in 10 people

• You may develop blood infections (septicemia) if your immune system is severely affected.If you notice fever, seek medical attention immediately.

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

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

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

• When Yondelis is used with PLD, you may experience syncope or fainting. Additionally, you may notice that your heart beats too fast or too hard (palpitations), experience 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 intense muscle pain and pain, stiffness, and muscle weakness. You may also experience a darkening of the urine color. All of the above may 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 may lead to kidney failure.If you experience intense muscle pain or weakness, seek medical attention immediately.

• You may experience difficulty breathing, irregular heart rhythm, decreased urine output, sudden changes in mental state, skin mottling, 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 develop abnormal fluid accumulation in the lungs, which causes swelling (pulmonary edema).

• You may experience general or partial swelling without apparent cause (edema), possibly accompanied by dizziness, vertigo, or thirst (low blood pressure). This may 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 your vein while it is being administered (extravasation). Therefore, you may experience redness, swelling, itching, and discomfort in the

injection site. If you experience any of these symptoms or signs,inform your doctor or nurse immediately.

This may 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. In the area, blisters, peeling, and darkening of the skin may appear. Before the extent of tissue damage becomes visible, it may take several days.Ifyou experience any of these symptoms or signs,seek medical attention immediately.

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

• You may experience yellow discoloration 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 be indicative of the liver's inability to perform its normal function. If you experience any of these symptoms or signs,seek medical attention immediately.

Other less severe side effects:

Very common: may affect more than 1 in 10 people

• You may:
• • feel tired

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

• You may experience headaches and sleep disturbances.

• You may experience mucosal inflammation, which presents as redness and swelling of the inside of the mouth that causes 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. It presents as redness of the skin on the palms of the hands, fingers, and soles of the feet, which, over time, may swell and turn purple. The lesions may be dry and peeling or in the form of blisters with ulceration.

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 experience dizziness, low blood pressure, and hot flashes or skin rash.

• You may experience more pronounced skin pigmentation in patients receiving Yondelis with PLD for ovarian cancer.

Reporting side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information about the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging and on the vial label after EXP. The expiration date is the last day of the month indicated.

Store in refrigerator (2°C-8°C).

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

Do not use this medication if you observe visible particles after reconstitution or dilution of the medication.

The disposal of unused medication and all materials that have been in contact with it will be carried out in accordance with local regulations for cytotoxic medications.

Composition of Yondelis

• 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 (to adjust the pH) and potassium hydroxide (to adjust the pH).

Appearance of the product and contents of the package

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

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

Holder of the marketing authorization and responsible for manufacturing

Pharma Mar, S.A.

Avda. de los Reyes 1

Polígono Industrial La Mina

28770 Colmenar Viejo (Madrid)

Spain

Phone: +34 91 846 60 00

Fax: +34 91 846 60 01

For more information about this medication, please contact the holder of the marketing authorization.

Last review date of this leaflet:

Other sources of information

The detailed information about this medication is available on the website of the European Medicines Agency: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 medications. The disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations for cytotoxic medications.

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

Preparation for intravenous infusion

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

Adequate aseptic techniques must be used.

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

When Yondelis is used in combination with DLP, the intravenous route must be thoroughly washed

with 50 mg/ml (5%) glucose solution for infusion after administration of DLP and before administration of Yondelis. The use for infusion of a diluent other than 50 mg/ml (5%) glucose solution may cause precipitation of DLP. (See also the summary of product characteristics of DLP, which contains specific instructions for its handling.)

Instructions for reconstitution

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

Yondelis 1 mg:inject 20 ml of sterile water for injection into the vial.

A syringe should be used to inject the correct amount of sterile water for injection into the vial. Shake the vial until the medication is completely dissolved. The reconstituted solution is transparent, 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.

Instructions for dilution

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:

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

0.05 mg/ml

SC = body surface area

Remove the appropriate amount of reconstituted solution from the vial; if intravenous administration is to be performed through a central venous route, 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 it is not possible to use a central venous route and a peripheral venous route must be used, the reconstituted solution must 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 parenteral solutions will be performed to detect the possible presence of particles. The prepared infusion solution must be administered immediately.

Stability of solutions during use

Reconstituted solution

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

From a microbiological point of view, the reconstituted solution must be diluted and used immediately. If it is not diluted and used immediately, the useful times and conditions for storage 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 was performed in validated and controlled aseptic conditions.

Diluted solution

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