Yondelis 0.25 mg powder for concentrate for solution forinfusion

Yondelis is an anti-cancer medicine that works by preventing the tumour cells from multiplying.

Yondelis is used for the treatment of patients with advanced soft tissue sarcoma, when previous medicines have been unsuccessful or the patients are unsuited to receive them. Soft tissue sarcoma is a malignant disease that starts somewhere in the soft tissues, such as the muscles, fat or other tissues (for example cartilages or vessels).

Yondelis in combination with pegylated liposomal doxorubicin (PLD: another anti-cancer medicine) is used for the treatment of patients with ovarian cancer that has come back after at least 1 previous therapy and are not resistant to platinum based anti-cancer medicines.

Do not use Yondelis:

• if you are allergic (hypersensitive) to trabectedin or any of the other ingredients of Yondelis.
• if you have any serious infections.
• if you are breast-feeding.
• if you will receive yellow fever vaccine.

Take special care with Yondelis:

Yondelis or its combination with PLD must not be used if you have severe liver or kidney damage. Tell your doctor if you know or suspect that you have any liver or kidney problems before starting the treatment with Yondelis.

You should seek medical attention immediately if any of the following conditions appear:

If you develop a fever as Yondelis may cause side-effects affecting your blood and liver.

If you still feel sick, vomit or are unable to drink fluids and therefore pass less urine despite being given anti-sickness medicines.

If you experience severe muscle pain or weakness as it could be a sign of damage to your muscles rhabdomyolysis see section 4.

If you notice that Yondelis infusion leaks out of your vein while you are being given it. It could lead to damage and death of your tissue cells around the injection site tissue necrosis, see also section 4 which may require surgery.

Yondelis must not be used in children and adolescents since safety and efficacy have not yet been studied in this age group.

Using other medicines

Please tell your doctor if you plan to take, are taking or have recently taken any other medicines, including medicines obtained without a prescription, vaccines and herbal medicines.

You must not use Yondelis if you will receive yellow fever vaccine and it is not recommended that you use Yondelis if you will receive a vaccine containing live virus particles. The effect of medicines containing phenytoin (for epilepsy) may be decreased if given together with Yondelis and this is therefore not recommended.

If you use other medicines, you may need to be closely monitored as the effects of Yondelis might be decreased (examples are medicines containing rifampicin (for bacterial infections), phenobarbital (for epilepsy) or St. John´s Wort ( Hypericum perforatum, an herbal medicine for depression)) or increased (examples are medicines containing ketoconazole or fluconazole (for fungal infections), ritonavir (for HIV infection), clarithromycin (for bacterial infections), aprepitant (to prevent nausea and vomiting), ciclosporin (inhibit the defensive system of the body) or verapamil (for high blood pressure and heart conditions)) as a result.

If you are given Yondelis or the combination Yondelis+PLD together with a medicine that might cause damage to the liver or to the muscles (rhabdomyolysis), you may need to be closely monitored, when using Yondelis together with this medicine, as there could be an increased risk of damage. Medicines containing statins (for lowering cholesterol levels and preventing cardiovascular disease) is an example of medicines that may cause muscle damage.

Using Yondelis with food and drink

Alcohol consumption must be avoided during treatment with Yondelis as this may harm the liver.

Pregnancy and breast-feeding

Pregnancy

You should not use Yondelis if you are pregnant or if you are trying to become pregnant as Yondelis may harm the unborn baby. If you are pregnant or you think you may be pregnant, you must tell your doctor immediately. The doctor may prescribe Yondelis during pregnancy in certain circumstances.

Adequate contraceptive precautions must be used by men in fertile age and women of childbearing potential when receiving Yondelis and for 3 months following the end of treatment for women and 5 months following the end of treatment for men. If a pregnancy should occur you must tell your doctor immediately and genetic counselling is recommended since Yondelis can cause genetic damage.

Genetic counselling is also recommended for patients wishing to have children after therapy. Male patients should seek advice on sperm conservation prior to treatment because of the risk of irreversible infertility due to therapy with Yondelis.

Breast-feeding

Yondelis must not be given to patients who are breast-feeding. Therefore you must stop breast-feeding before you start your treatment and you must not begin breast-feeding again until your doctor has confirmed that it is safe to do so.

Driving and using machines

During your treatment with Yondelis you may feel tired and experience a loss of strength. Do not drive or use any tools or machines if you are experiencing any of these side effects.

Important information about some of the ingredients of Yondelis

This medicine contains potassium, less than 1 mmol (39 mg) per vial, and can therefore be considered as essentially ?potassium-free?.

Yondelis is given to you under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic medicines.

For the treatment of soft tissue sarcoma, the usual dose is 1.5 mg/m 2 of body surface area. During the treatment period, your doctor will carefully monitor you and decide the most appropriate dosage of Yondelis to give to you.

For the treatment of ovarian cancer, the usual dose is 1.1 mg/m 2 body surface area after the administration of 30 mg/m 2 body surface area of PLD.

Before Yondelis is given to you, it is reconstituted and diluted for intravenous use. Every time you are given Yondelis for the treatment of soft tissue sarcoma, it will take about 24 hours for all of the solution to enter your blood. It will take 3 hours for the treatment of ovarian cancer.

In order to avoid irritation at the site of injection it is recommended that Yondelis is given to you through a central venous line.

You will be given medicine before and as needed during the treatment with Yondelis in order to protect your liver and to reduce the risk of side effects such as feeling sick (nausea) and vomiting.

The infusion is given to you every 3 weeks, although occasionally your doctor may recommend dose delays to ensure that you receive the most appropriate dosage of Yondelis.

The length of your whole treatment period will depend on your progress and how well you feel. Your doctor will tell you how long your treatment lasts. If you have any further questions on the use of this medicine, ask your doctor.

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

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

Side effects caused by the single treatment with Yondelis:

Very common (occurring in at least 1 in 10 patients):

You may feel tired feel short of breath dyspnoea bruise more easily have nose bleeds be more prone to infections. An infection could also give you a raised temperature fever. If you develop any of these symptoms you should seek medical attention immediately.

Your doctor may require blood tests in certain situations in order to avoid that you develop muscle damage rhabdomyolysis. In very severe cases this could lead to kidney failure. If you experience severe muscle pain or weakness, you should seek medical attention immediately.

You could have increased levels of the yellow pigment bilirubin in the blood which might cause jaundice a yellowing of the skin, mucous membranes and eyes.

You may experience headache and a loss of strength.

You may also lose your appetite, feel sick nausea or vomit, and become constipated. If you still feel sick, vomit or are unable to drink fluids and therefore pass less urine, despite being given anti-sickness medication, you should immediately seek medical help.

Your doctor will order regular blood tests to detect any abnormalities in the blood.

Common (occurring in at least 1 in 100 patients):

You may have fever. If you have a raised temperature you should seek medical attention immediately.

You could also feel pain in your back, muscles and joints. There could be damage to your nerves which may result in muscle pain, weakness and numbness. You could experience general swelling or swelling of the limbs and a sensation of creeping on the skin.

You may experience diarrhoea, loss of water from the body, inflammation of the mouth stomatitis, pain in the abdomen, weight loss, digestive discomfort and a change in your sense of taste.

You could have coughing.

You may lose hair alopecia.

You could also experience dizziness, sleeping problems, low blood pressure and flushing.

You may have a reaction at the site of injection. Yondelis infusion may leak out of your vein while you are being given it, leading to damage and death of your tissue cells around the injection site tissue necrosis, see also section 2 Take special care with Yondelis which may require surgery.

Other side effects that may occur with the combination of Yondelis and PLD:

When Yondelis is used in combination with PLD some of these side effects are more likely to occur and some may occcur in a more severe way.

Very common (occurring in at least 1 in 10 patients):

You may have the hand and foot syndrome. It may present as red skin of the palms, fingers, and soles of the feet that later may become swelling and violaceous. The lesions may either dry out and desquamate, or blister with ulceration.

Common (occurring in at least 1 in 100 patients):

You may have a higher skin pigmentation and rash. You could have mucosal inflammation as a swelling redness of the inside of the mouth leading to painful ulcers and mouth sores or as an inflammation of the gastrointestinal tract.

You may also have blood infections neutropenic infection and neutropenic sepsis. Your doctor will order regular blood tests to detect any abnormalities in the blood.

You may have syncope also called fainting.

You could have a weakness in the ventricles, the hearts major pumping chambers left ventricular dysfunction, sudden blockage in a lung artery pulmonary embolism and an abnormal build up of fluid in the lungs, which leads to swelling pulmonary oedema.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Keep out of the reach and sight of children.

Do not use Yondelis after the expiry date which is stated on the carton and the vial label after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2ºC - 8ºC).

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

What Yondelis contains:

• The active substance is trabectedin. Yondelis 0.25 mg: Each vial contains 0.25 mg of trabectedin. Yondelis 1 mg: Each vial contains 1 mg of trabectedin.
• The other ingredients are sucrose, potassium dihydrogen phosphate, phosphoric acid (for pH-adjustment) and potassium hydroxide (for pH-adjustment).

What Yondelis looks like and contents of the pack

Yondelis is a powder for concentrate for solution for infusion. The powder has a white to off-white colour and comes in a glass vial.

Each carton contains 1 vial of either 0.25 mg or 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

For any information about this medicine, please contact the Marketing Authorisation Holder.

This leaflet was last approved in

This medicinal product has been authorised under ?Exceptional Circumstances?. This means that due to the rarity of soft tissue sarcoma, it has not been possible to obtain complete information on Yondelis in this indication.

The European Medicines Agency (EMA) will review any new information on the medicine every year and this leaflet will be updated as necessary.

The following information is intended for medical or healthcare professionals only:

Instructions for use ? preparation, handling and disposal

Appropriate procedures for proper handling and disposal of cytotoxic medicines must be followed. Any unused medicine or waste material should be disposed of in accordance with local requirements for cytotoxic medicines.

You should have received training on the correct techniques to reconstitute and dilute Yondelis or its combination with PLD and you should wear protective clothing including mask, goggles and gloves during the reconstitution and dilution. Accidental contact with the skin, eyes or mucous membranes must be treated immediately with copious amounts of water. You should not work with this medicine if you are pregnant.

Preparation for intravenous infusion:

Yondelis must be reconstituted and further diluted prior to infusion (see also section 3). Appropriate aseptic techniques must be used.

Yondelis must not be administered as a mixture with other medicines in the same infusion apart from the diluent. No incompatibilities have been observed between Yondelis and type I glass bottles, polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, polyisoprene reservoirs and titanium implantable vascular access systems.

When Yondelis is used in combination with PLD, the intravenous line should be flushed well with 50 mg/ml (5%) glucose solution for infusion after administration of PLD and before administration of Yondelis. The use of any diluent other than 50 mg/ml (5%) glucose solution for infusion may cause precipitation of PLD. (See also PLD Summary Products Characteristics for specific handling instructions).

Instructions for reconstitution:

Yondelis 0.25 mg: Inject 5 ml of sterile water for injections into the vial.

Yondelis 1 mg: Inject 20 ml of sterile water for injections into the vial.

A syringe is used to inject the correct amount of sterile water for injections into the vial. Shake the vial until complete dissolution. The reconstituted solution results in a clear, colourless or slightly yellowish solution, essentially free of visible particles.

This reconstituted solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is for single-use only.

Instructions for dilution:

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

Volume ml BSA m2 x individual dose mgm2 0.05 mgml

BSA = Body Surface Area

Withdraw the appropriate amount of reconstituted solution from the vial. If administration is to be made via a central venous line, add the reconstituted solution to an infusion bag containing - 50 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion), the concentration of trabectedin in the infusion solution being ? 0.030 mg/ml.

If central venous access is not feasible and a peripheral venous line has to be used, add the reconstituted solution to an infusion bag containing - 1,000 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion).

Inspect the parenteral solution visually for particles prior to administration. Once the infusion is prepared, it should be administered immediately.

In-use stability of the solutions:

Reconstituted solution: After reconstitution, chemical and physical stability has been demonstrated for 30 hours up to 25ºC.

From a microbiological point of view, the reconstituted solution should be diluted and used immediately. If not diluted and used immediately, in-use storage times and conditions prior to use of the reconstituted solution are the responsibility of the user and would normally not be longer than 24 hours at 2ºC to 8ºC, unless reconstitution has taken place in controlled and validated aseptic conditions.

Diluted solution: After dilution, chemical and physical stability has been demonstrated for 30 hours up to 25ºC.