Trabectedin Accord: detailed information

Package leaflet: Information for the patient

Trabectedina Accord 0.25 mg powder for concentrate for solution for infusion, 1 mg powder for concentrate for solution for infusion

trabectedin
Please read this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor.
If you experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet

What Trabectedina Accord is and what it is used for
What you need to know before using Trabectedina Accord
How to use Trabectedina Accord
Possible side effects
How to store Trabectedina Accord
Contents of the pack and other information

1. What Trabectedin Accord is and what it is used for

Trabectedin Accord contains the active substance trabectedin. Trabectedin Accord is an anticancer medicine that prevents the multiplication of tumour cells.
Trabectedin Accord is used to treat patients with advanced soft tissue sarcoma who have not benefited from, or cannot be treated with, other medicines. Soft tissue sarcoma is a malignant disease that originates in any of the soft tissues, such as muscles, fat, or other tissues (e.g. cartilage or blood vessels).
Trabectedin Accord in combination with pegylated liposomal doxorubicin (PLD: another anticancer medicine) is used to treat patients with recurrent (returning) ovarian cancer after at least one previous therapy, and who are not resistant to platinum-containing anticancer medicines.

2. What you should know before using Trabectedin Accord

Do not use Trabectedin Accord

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 planning to receive the yellow fever vaccine.

Warnings and precautions
Talk to your doctor before using Trabectedin Accord.
Trabectedin Accord, either alone or in combination with PLD, must not be used if you have severe liver, kidney or heart damage.
Contact your doctor if you have or suspect any of the following conditions before starting treatment with Trabectedin Accord:

Liver or kidney problems.
Heart problems or a history of heart problems.
Left ventricular ejection fraction (LVEF) below the lower limit of normal.
If you have previously received high-dose anthracycline therapy.

Contact your doctor immediately if you experience any of the following:

If you have a fever, as Trabectedin Accord can cause side effects affecting blood and liver.
If you feel generally unwell, have vomiting or are unable to drink fluids, accompanied by reduced urine output despite anti-nausea medication.
If you experience severe muscle pain or weakness, which could be a sign of muscle damage (rhabdomyolysis: see section 4).
If the Trabectedin Accord solution leaks from the vein during infusion. This may cause tissue damage and destruction of cells around the injection site (tissue necrosis, see also section 4), which might require surgical removal of damaged tissue.
In case of an allergic reaction (hypersensitivity). In such a case, you may experience one or more of the following symptoms: fever, difficulty breathing, skin redness, flushing or rash, feeling unwell (nausea), or illness (vomiting; see section 4).
If you notice partial or generalized swelling (edema), possibly accompanied by dizziness, thirst, or lightheadedness (low blood pressure). This could be a sign of a condition (capillary leak syndrome) that causes excessive fluid accumulation in tissues and requires urgent medical evaluation.

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

Other medicines and Trabectedin Accord
Tell your doctor if you are taking, have recently taken, or might take any other medicines.
You must not use Trabectedin Accord if you are due to receive the yellow fever vaccine, and it is not recommended to use Trabectedin Accord if you are to receive a vaccine containing live viral particles. The effect of medicines containing phenytoin (for epilepsy) may be reduced when given together with Trabectedin Accord, and therefore their combination is not recommended.
If you are taking any of the following medicines during treatment with Trabectedin Accord, close monitoring is required, as the effects of Trabectedin Accord may be:

reduced (examples include medicines containing rifampicin (for bacterial infections), phenobarbital (for epilepsy), or St John’s wort (Hypericum perforatum, a herbal remedy for depression)), or
increased (examples include medicines containing ketoconazole or fluconazole (for fungal infections), ritonavir (for human immunodeficiency virus, HIV infections), clarithromycin (for bacterial infections), aprepitant (to prevent nausea and vomiting), cyclosporine (an immunosuppressant), or verapamil (for high blood pressure and heart conditions)).
Therefore, concomitant use of any of these medicines with Trabectedin Accord should be avoided if possible.
If you have been prescribed Trabectedin Accord or the combination Trabectedin Accord + PLD together with a medicine that may cause liver or muscle damage (rhabdomyolysis), close monitoring may be necessary, as there may be an increased risk of liver or muscle injury. Medicines containing statins (to lower cholesterol levels and prevent cardiovascular disease) are an example of medicines that can cause muscle injury.

Trabectedin Accord and alcohol
Avoid drinking alcohol during treatment with Trabectedin Accord, as it may cause liver damage.

Pregnancy, breastfeeding and fertility
Pregnancy
Trabectedin Accord must not be used during pregnancy. If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before taking this medicine.
Women of childbearing potential must use effective contraception during treatment with Trabectedin Accord and for 3 months after treatment.
If you become pregnant, inform your doctor immediately. Genetic counselling is recommended, as Trabectedin Accord may cause genetic damage.

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

Fertility
Men of reproductive potential must use effective contraception during treatment with Trabectedin Accord and for 5 months after treatment.
Patients are advised to consider possible egg or sperm preservation before treatment due to the risk of irreversible infertility caused by Trabectedin Accord therapy.
Genetic counselling is also recommended for all patients who wish to have children after therapy.

Driving and using machines
During treatment with Trabectedin Accord, you may experience fatigue and loss of strength. Do not drive or operate tools or machinery if you experience these side effects.

Trabectedin Accord contains potassium
This medicine contains less than 1 mmol (39 mg) of potassium per vial, i.e., essentially ‘potassium-free’.

3. How to use Trabectedina Accord

Trabectedina Accord is administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be restricted to qualified oncologists or other healthcare professionals specialized in the administration of cytotoxic medicinal products.

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 monitor you closely and determine the most appropriate dose of Trabectedina Accord for you. The recommended dose for Japanese patients is lower than the usual dose used in all other races and corresponds to 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, administered after pegylated liposomal doxorubicin (PLD) at a dose of 30 mg/m² of body surface area.

Before administration, Trabectedina Accord is reconstituted and diluted for intravenous infusion. Each time Trabectedina Accord is administered for the treatment of soft tissue sarcoma, the infusion will take approximately 24 hours to complete. For ovarian cancer treatment, the infusion will take 3 hours.

To avoid potential irritation at the injection site, administration of Trabectedina Accord through a central venous line is recommended.

You will be given certain medicinal products before treatment with Trabectedina Accord, and as needed during treatment, to protect the liver and reduce the risk of undesirable effects such as nausea and vomiting.

The infusion is repeated every 3 weeks, although occasionally your doctor may recommend delaying administration to ensure you receive the appropriate dose of Trabectedina Accord.

The total duration of treatment will depend on disease progression and your overall health status. Your doctor will decide how long your treatment should continue. If you have any questions about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine, or its combination with PLD, may cause side effects, although not everybody experiences them.
If you have any doubts about the side effects listed below, please consult your doctor for a more detailed explanation.

Serious side effects caused by treatment with Trabectedina Accord:

Very common: may affect more than 1 in 10 people

You may experience increased levels of the yellow pigment bilirubin in the blood, leading to jaundice (yellowing of the skin, mucous membranes, and eyes).
Your doctor will prescribe regular blood tests to detect any abnormalities in the blood.

Common: may affect up to 1 in 10 people

You may develop blood infections (sepsis) if your immune system is severely weakened. If you experience a rise in temperature, inform your doctor immediately.
You may experience muscle pain (myalgia). Nerve damage may also occur, causing muscle pain, weakness, and numbness. General swelling, swelling of the limbs, and a sensation of chills on the skin may also occur.
A reaction at the injection site may occur. The infusion solution containing Trabectedina Accord may leak from the vein during administration, causing damage and destruction of surrounding tissue cells (tissue necrosis; see also section 2 “Warnings and precautions”), which may require surgical intervention to remove the damaged tissue.
You may have an allergic reaction. In this case, you may experience fever, difficulty breathing, skin redness, flushing or skin rash, malaise (nausea), or vomiting.
When Trabectedina Accord is used in combination with PLD, fainting (syncope) may occur. Additionally, you may feel that your heart is beating too hard or too fast (palpitations), weakness in the ventricles—the main heart chambers responsible for pumping (left ventricular dysfunction)—or sudden blockage in a pulmonary artery (pulmonary embolism).

Uncommon: may affect up to 1 in 100 people

Severe muscle pain, stiffness, and muscle weakness may occur. You may also notice dark-colored urine. All the effects described above may be signs of muscle damage (rhabdomyolysis).
Your doctor may request blood tests in certain circumstances to prevent the development of muscle damage (rhabdomyolysis). In very severe cases, kidney failure may occur. 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, skin patches, extremely low blood pressure associated with abnormal laboratory results (reduced platelet count). If you experience any of the symptoms or signs listed above, seek immediate medical attention.
You may develop an abnormal accumulation of fluid in the lungs, causing swelling (pulmonary edema).
You may notice partial or generalized swelling (edema), possibly accompanied by drowsiness, dizziness, or thirst (low blood pressure). This could be a sign of a condition (capillary leak syndrome) that causes excessive fluid buildup in tissues. If you experience any of the symptoms or signs listed above, seek immediate medical attention.
Leakage of the Trabectedina Accord infusion solution from the vein (extravasation) may occur during infusion. In this case, you will notice redness, swelling, itching, and discomfort at the injection site. If you experience any of these symptoms or signs, inform the nurse or doctor immediately.

This situation may lead to damage or death of cells in the tissue surrounding the injection site (tissue necrosis), which may require surgical intervention.
Some symptoms or signs of extravasation may not become visible until several hours after they occur. The skin at the injection site may develop blisters, peeling, and dark discoloration. It may take several days before tissue damage becomes fully apparent. If you experience any of the symptoms or signs described above, seek immediate medical attention.

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 that the liver is unable to function properly. If you experience any of the symptoms or signs listed above, seek immediate medical attention.

Other less severe side effects

Very common: may affect more than 1 in 10 people

You may:
- feel tired
- experience shortness of breath and cough
- have back pain
- feel an excess of fluid in the body (edema)
- bruise very easily
- have nosebleeds
- be more prone to infections. An infection may also lead to a rise in temperature (fever). If you experience any of these symptoms, consult your doctor immediately.
You may experience digestive symptoms such as loss of appetite, nausea or vomiting, abdominal pain, diarrhea, or constipation. If you continue to feel generally unwell, have vomiting, or are unable to drink fluids despite anti-nausea medication, and have reduced urine output, contact your doctor immediately.
Headache may occur.
You may develop inflammation of mucous membranes, presenting as redness and swelling inside the mouth, leading to painful ulcers and inflammation in the mouth (stomatitis), or inflammation of the gastrointestinal tract when Trabectedina Accord is administered with PLD.
Female patients receiving Trabectedina Accord together with PLD for ovarian cancer may also develop hand-foot syndrome. This may present as skin redness on the palms, fingers, and soles of the feet, which may later swell and turn purplish. The lesions may either dry out and peel or form blisters with ulceration.

Common: may affect up to 1 in 10 people

Loss of body fluids, weight loss, digestive disturbances, and changes in taste sensation may occur.
You may lose your hair (alopecia).
Dizziness, low blood pressure, flushing, or skin rash may occur.
Female patients receiving Trabectedina Accord with PLD for ovarian cancer may develop increased skin pigmentation.
You may experience joint pain.
Sleep disturbances may occur.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please consult your doctor. You may also report side effects directly through the national reporting system listed in Annex V. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Trabectedina Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the label of the vial.
The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C-8 °C).
Information on the stability in use of reconstituted and diluted solutions is included in the section for
doctors and healthcare professionals.
Do not use this medicine if you notice visible particles after reconstitution or dilution.
Dispose of any unused product or waste material derived from this medicine according to local legal
requirements.

6. Package contents and other information

What Trabectedina Accord contains

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

Description of the appearance of Trabectedina Accord and contents of the pack
Trabectedina Accord is a powder for concentrate for solution for infusion. The powder is white to off-white in colour and is contained in a glass vial.
Each carton contains 1 vial of either 0.25 mg or 1 mg of trabectedin.

Marketing Authorisation Holder
Accord Healthcare S.L.U.
World Trade Center, Moll de Barcelona, s/n
Edifici Est, 6a Planta
08039 Barcelona
Spain

Manufacturers
Accord Healthcare Polska Sp.z.o.o.
Ul. Lutomierska 50,
95-200, Pabianice, Poland
Or
Pharmadox Healthcare Ltd.
KW20A Kordin Industrial Park,
Paola, PLA3000, Malta
Or
Accord Healthcare Single Member S.A.
64th Km National Road Athens, Lamia, 32009, Greece

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
AT / BE / BG / CY / CZ / DE / DK / EE / ES / FI / FR / HR / HU / IE / IS / IT / LT / LV / LU / MT /
NL / NO / PL / PT / RO / SE / SI / SK
Accord Healthcare S.L.U.
Tel: +34 93 301 00 64
EL
Win Medica Α.Ε.
Tel: +30 210 74 88 821

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

Instructions for use, preparation, handling, and disposal
Appropriate procedures must be followed for the correct handling and disposal of cytotoxic medicinal products. Unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations for cytotoxic drugs.
Adequate training in the proper techniques for reconstitution and dilution of Trabectedina Accord or its combination with PLD must be provided, and protective clothing—including mask, gloves, and goggles—must be worn during reconstitution and dilution. Any accidental contact with the skin, eyes, or mucous membranes must be immediately rinsed with copious amounts of water. This medicinal product must not be handled during pregnancy.

Preparation for intravenous infusion
Trabectedina Accord must be reconstituted and then diluted prior to infusion (see also section 3). Appropriate aseptic techniques must be used.
Trabectedina Accord must not be administered mixed in the same infusion with medicinal products other than its designated diluent. No incompatibility has been observed between Trabectedina Accord and type I glass vials, polyvinyl chloride (PVC) and polyethylene (PE) bags and tubing, polystyrene reservoirs, or titanium implantable vascular access systems.

When Trabectedina Accord is used in combination with PLD, the intravenous infusion line must be thoroughly flushed with 5% glucose solution for infusion (50 mg/mL) after administration of PLD and before administration of Trabectedina Accord. Use of a diluent other than 5% glucose solution for infusion (50 mg/mL) may cause precipitation of PLD. (For specific handling instructions, refer also to the Summary of Product Characteristics of PLD.)

Instructions for reconstitution
Trabectedina Accord 0.25 mg: Inject 5 mL of sterile water for injection into the vial.
Trabectedina Accord 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 complete dissolution is achieved. The reconstituted solution is clear and colorless or slightly yellowish, essentially free from 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 9 mg/mL (0.9%) sodium chloride solution or 50 mg/mL (5%) glucose solution for infusion. Calculate the required volume as follows:
Volume (mL) = BSA (m²) × individual dose (mg/m²)
0.05 mg/mL
BSA = Body Surface Area
Withdraw the appropriate volume of reconstituted solution from the vial. If intravenous administration is to be performed via a central venous line, the reconstituted solution must be added to an infusion bag containing ≥ 50 mL of diluent (9 mg/mL (0.9%) sodium chloride solution or 50 mg/mL (5%) glucose solution for infusion), with a trabectedin concentration in the infusion solution ≤ 0.030 mg/mL.
If central venous access is not feasible and a peripheral venous line must be used, add the reconstituted solution to an infusion bag containing ≥ 1,000 mL of diluent (9 mg/mL (0.9%) sodium chloride solution or 50 mg/mL (5%) glucose solution for infusion).
Prior to intravenous administration, visually inspect the parenteral solution for the presence of particles. Once the infusion is prepared, administer it immediately.

In-use stability of solutions
Reconstituted solution
Chemical and physical stability has been demonstrated for 30 hours at temperatures from 20 °C to 25 °C and from 2 °C to 8 °C.
From a microbiological standpoint, the reconstituted solution should be diluted and used immediately. Otherwise, the in-use storage times and conditions prior to use are the responsibility of the user and should not exceed 24 hours at 2 °C to 8 °C, unless reconstitution was performed under controlled and validated aseptic conditions.

Diluted solution
After dilution, chemical and physical stability has been demonstrated for 30 hours up to 25 °C.
From a microbiological standpoint, unless the method of opening/reconstitution/dilution excludes the risk of microbial contamination, the product must be used immediately. Otherwise, the user is responsible for the in-use storage times and conditions.