Yondelis 0.25 mg powder for concentrate for solution for infusion

Package leaflet: Information for the user

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 the entire 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 adverse reactions, consult your doctor, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

1. What Yondelis is and what it is used for

2. What you need to know before using Yondelis

3. How to use Yondelis

4. Possible adverse effects

5. How to store Yondelis

6. Contents of the pack and other information

1. What Yondelis is and what it is used for

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

Yondelis is used to treat patients with advanced soft tissue sarcoma when previous treatment with other medicines has not been effective or when patients cannot receive other medicines. Soft tissue sarcoma is a malignant neoplasm that starts in areas of soft tissue, such as muscles, fat, or other tissues (e.g., cartilage or blood vessels).

Yondelis in combination with pegylated liposomal doxorubicin (PLD, another antitumour medicine) is used to treat patients with ovarian cancer who have relapsed after at least one prior treatment and who are not resistant to platinum-containing anticancer medicines.

2. What you need to know before using Yondelis

Do not use Yondelis

• if you are allergic to trabectedin or to 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 due to receive the yellow fever vaccine.

Warnings and precautions

Talk to your doctor before starting treatment with Yondelis.

You must not use Yondelis or the combination of Yondelis with DLP if you have severe liver, kidney, or heart problems.

Talk to 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.

• Have previously received treatment with high doses of anthracyclines.

Seek immediate medical attention if any of the following occur:

• If you develop fever, as Yondelis may cause side effects affecting the blood and liver.

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

• If you experience severe muscle pain or weakness, as this could be a sign of muscle damage (rhabdomyolysis, see section 4).

• If you notice leakage of the Yondelis infusion from the vein during administration. This could damage or destroy cells in nearby tissues (tissue necrosis; see also section 4), which might 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, skin redness or rash, dizziness (nausea), or feeling unwell (vomiting, see section 4).

• If you notice unexplained generalized or localized swelling (edema), possibly accompanied by dizziness, vertigo, or thirst (low blood pressure). This could be a sign of a disorder (capillary leak syndrome) that causes excessive fluid accumulation in your tissues and requires urgent clinical evaluation by your doctor.

Children and adolescents

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

Other medicines and Yondelis

Inform your doctor if you are taking, have recently taken, or might need to take any other medicines.

You must not use Yondelis if you are due to receive the yellow fever vaccine. The use of Yondelis is also not recommended if you are to receive a vaccine containing live virus particles. The use of medicines containing phenytoin (for epilepsy) together with Yondelis is not recommended, as the effect of phenytoin may be reduced.

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

• reduced (for example, when taking medicines containing rifampicin (for bacterial infections), phenobarbital (for epilepsy), or St. John’s wort (Hypericum perforatum, a herbal remedy used for depression)), or

• increased (for example, medicines containing ketoconazole or fluconazole (for fungal infections), ritonavir (for human immunodeficiency virus [HIV] infection), clarithromycin (for bacterial infections), aprepitant (to prevent nausea and vomiting), cyclosporine (to suppress the immune system), or verapamil (for hypertension and other heart conditions)).

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

If you are receiving another medicine alongside Yondelis or the combination of Yondelis and DLP that may cause liver damage or muscle damage (rhabdomyolysis), you may be monitored closely, as this could increase the risk of liver or muscle injury. Medicines containing statins (to reduce cholesterol levels and prevent cardiovascular disease) are an example of medicines that may cause muscle damage.

Use of Yondelis with alcohol

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

Pregnancy, breastfeeding, and fertility

Pregnancy

Yondelis must 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 potential must use effective contraception during treatment with Yondelis and for 3 months after treatment has ended.

If you become pregnant, inform your doctor immediately. Genetic counseling is also recommended, as Yondelis may cause genetic damage to the fetus.

Breastfeeding

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

Fertility

Men of reproductive potential must use effective contraception during treatment with Yondelis and for 5 months after treatment.

Because there is a risk that treatment with Yondelis may cause irreversible infertility, patients are advised to seek counseling about the possibility of preserving 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 operate tools or machinery if you experience any of these side effects.

Yondelis contains potassium

This medicine contains less than 1 mmol (39 mg) of potassium per vial, which is essentially “potassium-free”.

3. How to use Yondelis

Yondelis must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be restricted to qualified oncologists and other healthcare professionals specialized in the administration of cytotoxic drugs.

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 monitor you closely and determine the most appropriate 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.

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

Before administration, Yondelis must be reconstituted and diluted for intravenous use. Each time Yondelis is administered for the treatment of soft tissue sarcoma, it will take approximately 24 hours for the entire solution to enter your bloodstream. Ovarian cancer treatment will last 3 hours.

To avoid irritation at the injection site, 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 whenever needed during treatment.

You will receive an infusion every 3 weeks, although occasionally your doctor may recommend delaying doses in order to ensure you receive the most appropriate dose of Yondelis.

The total duration of treatment will depend on your response and how you feel. Your doctor will inform you how long your treatment may last. If you have any further questions about the use of this medicine, ask your doctor.

4. Possible adverse effects

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

If you are unsure about any of the following effects listed below, please ask your doctor to explain them in more detail.

Serious adverse 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 could lead to 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 develop blood infections (sepsis) if your immune system is severely compromised. If you develop fever, contact your doctor immediately.

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

• You may have a reaction at the injection site. Yondelis infusion may leak out of the vein during administration, causing injury and destruction of cells in nearby tissues (tissue necrosis; see also section 2 “Warnings and precautions”), which might require surgical intervention.

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

• When Yondelis is used together with PLD, you may experience fainting or collapse. Additionally, you may notice your heart beating too hard or too fast (palpitations), weakness in the ventricles—the main pumping chambers of the heart (left ventricular dysfunction)—or sudden blockage of a pulmonary artery (pulmonary embolism).

Uncommon: may affect up to 1 in 100 people

• You may experience severe muscle pain and muscle pain, stiffness, and weakness. You may also notice darkening of the urine. All of the above could be signs of muscle damage (rhabdomyolysis).

• Your doctor may request blood tests in certain situations to prevent muscle damage (rhabdomyolysis). In some very severe cases, such muscle damage could lead to kidney failure. If you experience severe muscle pain or weakness, contact your doctor immediately.

• You may experience difficulty breathing, irregular heartbeat, reduced urine output, sudden changes in mental status, mottled skin areas, very low blood pressure associated with abnormal laboratory results (decreased platelet count). If you experience any of these symptoms or signs, contact your doctor immediately.

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

• You may notice general or localized 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 excessive fluid accumulation in your tissues. If this occurs, contact your doctor immediately.

• It is possible that you notice Yondelis infusion leaking out of your vein during administration (extravasation). Therefore, you may notice redness, swelling, itching, and discomfort at the

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

This could lead to damage and death of the surrounding tissue cells at the injection site (tissue necrosis), which might require surgery.

Some of the symptoms or signs of extravasation may not be visible until several hours after it occurred. Blisters, peeling, and darkening of the skin may appear at the site. Several days may pass before the extent of tissue damage becomes visible. If you experience any of these symptoms or signs, contact your doctor immediately.

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

• You may experience yellowing of the skin and whites of the eyes (jaundice), pain in the upper right part of the abdomen, nausea, vomiting, general malaise, difficulty concentrating, disorientation, or confusion, and drowsiness. These signs may indicate the liver’s inability to perform its normal functions. If you experience any of these symptoms or signs, contact your doctor immediately.

Other less serious adverse effects:

Very common: may affect more than 1 in 10 people

• You may:

  • feel tired

• experience difficulty breathing and cough

• feel back and joint pain

• have excess fluid in the body (edema)

• develop bruises (bruising) more easily

• have nosebleeds

• be more prone to infections. An infection may also cause fever. If you experience any of these symptoms, contact your doctor immediately.

• You may also experience gastrointestinal symptoms such as decreased appetite, nausea or vomiting, abdominal pain, diarrhea, or constipation. If you continue to have nausea, vomit, or are unable to drink fluids—and therefore urinate less—despite taking anti-vomiting medication, contact your doctor immediately.

• You may experience headache and sleep disturbances.

• You may develop mucositis, which presents as redness and swelling of the lining of the mouth leading to painful ulcers and sores (stomatitis), or inflammation of the gastrointestinal tract when Yondelis is used together with PLD.

• Female patients receiving Yondelis together with PLD for ovarian cancer may also develop hand-foot syndrome. This presents as redness of the skin on the palms of the hands, fingers, and soles of the feet, which may later swell and turn purplish. The lesions may be dry and scaly or blistering with ulceration.

Common: may affect up to 1 in 10 people

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

• You may lose hair (alopecia).

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

• Increased skin pigmentation may occur in patients receiving Yondelis together with PLD for ovarian cancer.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor, even if they are possible adverse effects not listed in this leaflet. You may also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Yondelis

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiry date stated on the pack and on the label of the vial after EXP. The expiry date refers to the last day of the month indicated.

Store in a refrigerator (2°C-8°C).

Information on the stability of reconstituted and diluted solutions is provided in the section for medical and healthcare professionals.

Do not use this medicine if visible particles are observed after reconstitution or dilution.

Disposal of unused medicine and of all materials that have been in contact with it must be carried out in accordance with local regulations for cytotoxic medicines.

6. Package contents and other information

Composition of Yondelis

• The active substance 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 pH) and potassium hydroxide (to adjust pH).

Appearance of the product and contents of the container

Yondelis is a powder for concentrate for solution for infusion. The powder is white or almost white and is supplied in a glass vial.

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

Marketing Authorisation 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 is available upon request to the Marketing Authorisation Holder.

Date of the most recent review 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 for healthcare professionals only:

Instructions for use, preparation, handling and disposal

Appropriate procedures for the safe handling and disposal of cytotoxic medicinal products must be followed. Any unused medicine and materials that have come into contact with it should be disposed of in accordance with local regulations for cytotoxic drugs.

Healthcare professionals must have received training in the correct techniques for reconstitution and dilution of Yondelis or its combination with DLP. During reconstitution and dilution, protective clothing, including mask, protective goggles and gloves, must be worn. Pregnant individuals should not handle this medicinal product.

Preparation for intravenous infusion

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

Appropriate aseptic techniques must be used.

Yondelis must not be administered mixed with other medicinal products except the diluent in the same infusion. No incompatibilities have been observed between Yondelis and type I glass vials, poly(vinyl chloride) (PVC) and polyethylene (PE) bags and tubing, polyisoprene reservoirs or titanium implantable vascular access systems.

When Yondelis is used in combination with DLP, the intravenous line must be thoroughly flushed
with 50 mg/ml (5 %) glucose solution for infusion after administration of DLP and before administration of Yondelis. Using a diluent other than 50 mg/ml (5 %) glucose solution for infusion may cause precipitation of DLP. (See also the Summary of Product Characteristics for 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.

Use a syringe to inject the correct volume of sterile water for injection into the vial. Shake the vial until the drug is completely dissolved. The reconstituted solution is clear, colourless or slightly yellowish, and free from visible particles.

The reconstituted solution has a concentration of 0.05 mg/ml of trabectedin. Further dilution is required, and the solution is intended for single use only.

Instructions for dilution

Dilute the reconstituted solution with either 9 mg/ml (0.9 %) sodium chloride solution for infusion or 50 mg/ml (5 %) glucose solution for infusion. Calculate the required volume as follows:

Volume (ml) = BSA (m²) × individual dose (mg/m²)