Trabectedin Ever Pharma 0.25 mg powder for concentrate for solution for infusion EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

Trabectedin EVER Pharma 0.25 mg powder for concentrate for solution for infusion EFG.

Trabectedin EVER Pharma 1 mg powder for concentrate for solution for infusion EFG.

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

Package leaflet

1. What Trabectedina EVER Pharma is and what it is used for
2. What you need to know before using Trabectedina EVER Pharma
3. How to use Trabectedina EVER Pharma
4. Possible side effects
5. How to store Trabectedina EVER Pharma
6. Contents of the pack and other information

1. What Trabectedina EVER Pharma is and what it is used for

Trabectedina EVER Pharma contains trabectedin as the active substance. Trabectedina EVER Pharma is an anticancer medicinal product that works by preventing the multiplication of tumour cells.

Trabectedin is used for the treatment of patients with advanced soft tissue sarcoma when previous treatment with other medicinal products has not been effective or when patients cannot be treated with other medicinal products. Soft tissue sarcoma is a malignant neoplasm that originates in soft tissues, such as muscles, fat, or other tissues (e.g., cartilage or blood vessels).

Trabectedin in combination with pegylated liposomal doxorubicin (PLD, another antineoplastic medicinal product) is used for the treatment of patients with ovarian cancer who have experienced relapse after at least one prior therapy and who are not platinum-resistant.

2. What you need to know before starting to use Trabectedin EVER Pharma

Do not use trabectedin EVER Pharma

• 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 trabectedin.

You must not use trabectedin or its combination with DLP if you have severe problems with your liver, kidneys, or heart.

Consult your doctor before starting 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.
• Have previously received treatment with high doses of anthracyclines.

Seek medical attention immediately if any of the following occur:

• If you develop fever, as trabectedin 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 medical attention immediately.

• If you experience 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 leaks out of 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, redness or flushing of the skin or rash, feeling dizzy (nausea), or feeling unwell (vomiting, see section 4).

• If you notice generalized or partial swelling without apparent cause (edema), possibly accompanied by dizziness, vertigo, or thirst (low blood pressure). This could indicate a disorder (capillary leak syndrome) that causes excessive fluid accumulation in your tissues and requires urgent clinical evaluation by your doctor.

Children and adolescents

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

Other medicines and Trabectedin EVER Pharma

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

You must not use trabectedin if you are to be vaccinated against yellow fever, and its use is also not recommended if you are to receive a vaccine containing live virus particles. The use of medications containing phenytoin (for the treatment of epilepsy) together with trabectedin is not recommended, as the effect of phenytoin may be reduced.

If you are taking any of the following medicines during your treatment with trabectedin, you will need to be closely monitored because the effects of Trabectedin EVER Pharma may be:

• reduced (e.g., when using medicines containing rifampicin (for bacterial infections), phenobarbital (for epilepsy), or St. John’s wort (Hypericum perforatum, a herbal remedy used for the treatment of depression)), or

• increased (e.g., 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 (which suppress the body's immune system), or verapamil (for high blood pressure and other heart conditions)).

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

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

Use of Trabectedin EVER Pharma with alcohol

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

Pregnancy, breastfeeding, and fertility

Pregnancy

Trabectedin 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 trabectedin and for 3 months after treatment has ended.

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

Breastfeeding

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

Fertility

Men of reproductive age must use effective contraception during treatment with trabectedin and for 5 months after treatment ends.

Because there is a risk that treatment with trabectedin may cause irreversible infertility, patients are advised to seek counseling regarding 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 use of machines

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

Trabectedin EVER Pharma contains sodium

This medicine contains sodium, less than 1 mmol (23 mg) per vial; hence, it is essentially “sodium-free”.

3. How to use Trabectedin EVER Pharma

Trabectedin 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 trabectedin 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, 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 infused into your bloodstream. The treatment for ovarian cancer will last 3 hours.

To avoid irritation at the injection site, it is advisable to administer trabectedin 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 trabectedin and whenever needed during treatment.

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

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

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service at 91 562 04 20, indicating the medication and the amount ingested.

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 terms used in the following list, please ask your doctor for a more detailed explanation.

Serious adverse effects caused by treatment with Trabectedin EVER Pharma:

Very common: may affect more than 1 in 10 people

• You may have elevated levels of the yellow pigment bilirubin in your 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 may also suffer nerve damage, which causes muscle pain, weakness, and numbness. You may experience general or limb swelling and skin tingling sensations.

• You may have a reaction at the injection site. Trabectedin 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 may require surgical intervention.

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

• When trabectedin is used together with PLD, you may experience fainting or collapse. In addition, you may notice your heart beating too strongly or too fast (palpitations), weakness in the ventricles—the heart’s main pumping chambers (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 pain, stiffness, and muscle weakness. You may also notice darkening of the urine color. The above symptoms could be signs of muscle damage (rhabdomyolysis).

• Your doctor may request blood tests in certain situations to help prevent muscle damage (rhabdomyolysis). In 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 abnormal fluid accumulation 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.

• You may notice that the trabectedin infusion leaks out of your vein during administration (extravasation). Therefore, you may experience 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 surrounding tissue cells (tissue necrosis), which may require surgery.

Some symptoms or signs of extravasation may not become visible until several hours after the event. Blisters, peeling, and skin discoloration may appear at the site. Several days may pass before the full 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, 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 pain
  • have excess fluid in the body (edema)
  • develop bruises (hematomas) 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-nausea medication, contact your doctor immediately.

• You may experience headache.

• You may develop mucosal inflammation, which may present as redness and swelling inside the mouth causing painful ulcers and sores (stomatitis), or as gastrointestinal tract inflammation when Trabectedin EVER Pharma is used together with PLD.

• Female patients receiving Trabectedin EVER Pharma 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. Lesions may be dry and peeling or appear as blisters with ulceration.

Common: may affect up to 1 in 10 people

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

• 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 Trabectedin EVER Pharma together with PLD for ovarian cancer.

• You may feel joint pain.

• You may experience sleep disturbances.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Trabectedin EVER Pharma

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

Do not use this medicine after the expiry date stated on the packaging and 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 during use is included 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 come into contact with it must be carried out in accordance with local regulations for cytotoxic medicines.

6. Contents of the container and additional information

Composition of Trabectedin EVER Pharma

• The active substance is trabectedin.

Trabectedin EVER Pharma 0.25 mg: each vial of powder contains 0.25 mg of trabectedin.

Trabectedin EVER Pharma 1 mg: each vial of powder contains 1 mg of trabectedin.

• The other components are citric acid (E330), arginine, concentrated phosphoric acid (for pH adjustment) (E338), and sodium hydroxide (for pH adjustment) (E524).

Appearance of the product and contents of the pack

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

The 0.25 mg trabectedin glass vial is closed with a rubber stopper sealed with a blue flip-off aluminum cap.

The 1 mg trabectedin glass vial is closed with a rubber stopper sealed with a pink flip-off aluminum cap.

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

Marketing Authorization Holder

EVER Valinject GmbH
Oberburgau 3
4866 Unterach am Attersee
Austria

Manufacturer

EVER Pharma Jena GmbH
Otto-Schott-Str. 15
07745 Jena
Germany

EVER Pharma Jena GmbH
Brüsseler Str. 18
07747 Jena
Germany

Local Representative

EVER Pharma Therapeutics Spain, S.L.
C/Toledo 170
28005 Madrid
Spain

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Date of the most recent review of this leaflet: 04/24

Other sources of information

Detailed information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS): http://www.aemps.gob.es/.

This information is intended for healthcare professionals only:

Instructions for use, preparation, handling, and disposal

Appropriate procedures must be followed for the proper handling and disposal of cytotoxic medicinal products. Unused medicinal product and all materials that have come into contact with it must be disposed of in accordance with local regulations for cytotoxic medicinal products.

Healthcare professionals must have received training in the correct techniques for reconstitution and dilution of Trabectedina EVER Pharma or its combination with DLP. During reconstitution and dilution of the drug, protective clothing including a mask, protective goggles, and gloves must be worn. If you are pregnant, you must not handle this medicinal product.

Preparation for intravenous infusion

Trabectedina EVER Pharma must be reconstituted and subsequently diluted prior to infusion (see also section 3). Appropriate aseptic techniques must be used.

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

When Trabectedina EVER Pharma 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 Trabectedina EVER Pharma. 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 regarding its handling.)

Reconstitution instructions

Trabectedina EVER Pharma 0.25 mg: Inject 5 ml of sterile water for injection into the vial.

Trabectedina EVER Pharma 1 mg: Inject 20 ml of sterile water for injection into the vial.

A syringe must be used 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 product is intended for single use only.

Dilution instructions

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)