Tuznue

Package leaflet: Information for the user

Tuznue 150 mg powder for concentrate for solution for infusion, 420 mg powder for concentrate for solution for infusion

trastuzumab
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
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, consult your doctor or pharmacist.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Tuznue is and what it is used for
2. What you need to know before being given Tuznue
3. How Tuznue is administered
4. Possible side effects
5. How to store Tuznue
6. Contents of the pack and other information

1. What Tuznue is and what it is used for

Tuznue contains the active substance trastuzumab, which is a monoclonal antibody.
Monoclonal antibodies bind to specific proteins or antigens. Trastuzumab is designed to selectively bind
to an antigen called human epidermal growth factor receptor 2 (HER2).
HER2 is present in high amounts on the surface of certain tumor cells and stimulates their growth.
When Tuznue binds to HER2, it blocks the growth of these cells and causes their death.
Your doctor may prescribe Tuznue for the treatment of breast and gastric cancer if:

• you have early-stage breast cancer with high levels of a protein called HER2
• you have metastatic breast cancer (breast cancer that has spread away from the primary tumor) with high levels of HER2. Tuznue may be prescribed in combination with the chemotherapeutic medicines paclitaxel or docetaxel as first treatment for metastatic breast cancer, or it may be prescribed alone when other treatments have proven ineffective. It is also used in combination with medicines called aromatase inhibitors for the treatment of patients with high levels of HER2 and metastatic breast cancer with hormone receptor-positive (cancer that is sensitive to female sex hormones).
• you have metastatic gastric cancer with high levels of HER2, in combination with other anticancer medicines capecitabine or 5-fluorouracil and cisplatin.

2. What you need to know before you are given Tuznue

Do not use Tuznue if

• you are allergic to trastuzumab, mouse proteins (murine proteins), or any of the other ingredients of this medicine (listed in section 6).
• you have severe breathing problems at rest due to tumour or require oxygen treatment.

Warnings and precautions
Your doctor will closely monitor you during treatment.
Heart checks
Treatment with Tuznue, given alone or in combination with a taxane, may affect the heart,
especially if you have previously received an anthracycline (taxanes and anthracyclines are two other types of
medicines used to treat cancer). The effects may range from moderate to severe and could lead to death.
Heart function will therefore be checked before, during (every three months), and after (up to two to five years)
treatment with Tuznue. If you develop signs of heart failure (i.e. the heart's inability to pump blood adequately),
you may require more frequent monitoring of heart function (every six to eight weeks), may receive treatment
for heart failure, or may need to discontinue treatment with Tuznue.
Talk to your doctor, pharmacist, or nurse before you are given Tuznue if:

• you have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high blood pressure, or if you have taken or are currently taking any medicine to treat high blood pressure.
• you have taken or are currently taking a medicine called doxorubicin or epirubicin (medicines used to treat cancer). These medicines (or any other anthracycline) can damage heart muscle and increase the risk of heart problems when taking Tuznue.
• you suffer from shortness of breath, particularly if you are currently receiving a taxane. Tuznue can cause difficulty breathing, especially the first time it is administered. This may be more serious if you already have breathing difficulties. Very rarely, patients with severe breathing difficulties before treatment have died after receiving Tuznue.
• you have received other cancer treatments.

If you are receiving Tuznue in combination with any other cancer medicine, such as paclitaxel, docetaxel, an aromatase inhibitor, capecitabine, 5-fluorouracil, or cisplatin, you should also read the package leaflet of these medicines.
Children and adolescents
Tuznue is not recommended for use in individuals under 18 years of age.
Other medicines and Tuznue
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other medicines.
It may take up to 7 months for Tuznue to be eliminated from the body. Therefore, inform your doctor, pharmacist, or nurse that you have been administered Tuznue if you start taking any new medicine within 7 months after stopping treatment.
Pregnancy

• If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, inform your doctor, pharmacist, or nurse before taking this medicine.
• You must use effective contraception during treatment with Tuznue and for at least 7 months after the end of treatment.
• Your doctor will discuss with you the risks and benefits of taking Tuznue during pregnancy. In rare cases, women treated with trastuzumab during pregnancy have shown reduced levels of amniotic fluid surrounding the developing baby in the womb. This condition may harm the unborn baby and has been associated with incomplete lung development, which has led to fetal death.

Breastfeeding
Do not breastfeed during treatment with Tuznue and for 7 months after the last dose of Tuznue, as Tuznue may pass into breast milk.
A Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Tuznue may affect your ability to drive or operate machinery. If you develop symptoms such as dizziness, drowsiness, chills, or fever during treatment, you should not drive or operate machinery until these symptoms have resolved.

3. How Tuznue is administered

Before starting treatment, your doctor will determine the amount of HER2 in the tumour. Only patients with high levels of HER2 will be treated with Tuznue. This medicine must be administered only by a doctor or nurse. Your doctor will prescribe the dose and treatment schedule appropriate for you. The dose of Tuznue depends on your body weight.
Tuznue is given as an intravenous infusion (intravenous infusion, “drip”). This intravenous formulation is not intended for subcutaneous use and must be administered exclusively via intravenous infusion.
The first dose of treatment is administered over a period of 90 minutes, during which you will be monitored by a healthcare professional in case you experience any adverse effects (see section 2 “Warnings and precautions”). If the first dose is well tolerated, subsequent doses may be administered over a period of 30 minutes. The number of infusions you will receive depends on your response to treatment. Your doctor will discuss this with you.
To avoid medication errors, it is important to check the labels on the vials to ensure that the medicine being prepared and administered is Tuznue (trastuzumab) and not another trastuzumab-containing medicine (e.g. trastuzumab emtansine or trastuzumab deruxtecan).
In patients with early breast cancer, metastatic breast cancer, and metastatic gastric cancer, Tuznue is administered every 3 weeks. This medicine may also be administered once weekly for the treatment of metastatic breast cancer.
If you interrupt treatment with Tuznue
Do not stop taking this medicine without first discussing it with your doctor. All doses must be taken at the correct time, either weekly or every three weeks (depending on the treatment schedule). This allows the medicine to work optimally.
It may take up to 7 months for this medicine to be eliminated from the body. Therefore, your doctor may decide to continue monitoring heart function even after treatment has ended.
If you have any questions about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. Some of these side effects can be serious and may require hospitalisation.
During infusion of Tuznue, reactions such as chills, fever and other flu-like symptoms may occur. These effects are very common (may affect more than 1 in 10 people).
Other infusion-related symptoms include: nausea, vomiting, pain, increased muscle tension and tremors, headache, dizziness, breathing difficulties, high or low blood pressure, heart rhythm disorders (palpitations, rapid or irregular heartbeat), facial or lip swelling, skin rashes and feeling of fatigue. Some of these symptoms can be severe, and some patients have died (see section 2 “Warnings and precautions”).
These effects occur mainly with the first intravenous infusion (“drip” into the vein) and during the first hours after the start of the infusion. They are usually temporary. You will be monitored by a healthcare professional during the infusion and for at least six hours after the start of the first infusion and for two hours after the start of subsequent infusions. If you experience a reaction, the infusion will be slowed down or stopped, and you may be given treatment to counteract the side effects. The infusion may be resumed once symptoms have improved.
Occasionally, symptoms begin more than six hours after the start of the infusion. If this happens to you, contact your doctor immediately. Sometimes, symptoms may improve and then worsen later.

Serious side effects
Other side effects may occur at any time during treatment with this medicine, not only in relation to an infusion. Tell your doctor or nurse immediately if you notice any of the following side effects:

• Heart problems, which may sometimes be serious, can occur during treatment and occasionally after it has been stopped. These include weakening of the heart muscle which may lead to heart failure, inflammation of the lining of the heart, and heart rhythm disorders. These may cause symptoms such as shortness of breath (including at night), cough, fluid retention (swelling) in the legs or arms, and palpitations (rapid or irregular heartbeat) (see section 2, “Cardiac monitoring”).

Your doctor will monitor your heart regularly during and after treatment, but you must inform your doctor immediately if you notice any of the symptoms listed above.

• Tumour lysis syndrome (a group of metabolic complications occurring after anti-tumour treatment, characterised by high levels of potassium and phosphate in the blood and low levels of calcium in the blood). Symptoms may include kidney problems (weakness, shortness of breath, fatigue, and confusion), heart problems (rapid or slow heartbeat), seizures, vomiting or diarrhoea, and tingling around the mouth, hands or feet.

If you experience any of the above symptoms after completing treatment with Tuznue, you must see a doctor and inform them about your previous treatment with Tuznue.

Very common side effects (may affect more than 1 in 10 people):

• infections
• diarrhoea
• constipation
• heartburn (dyspepsia)
• fatigue
• rashes
• chest pain
• abdominal pain
• joint pain
• low red and white blood cell counts (which help fight infections), sometimes associated with fever
• muscle pain
• conjunctivitis
• excessive tearing
• nosebleeds
• runny nose
• hair loss
• tremor
• hot flushes
• dizziness
• nail problems
• weight loss
• loss of appetite
• inability to sleep (insomnia)
• altered taste
• low platelet count
• bruising
• numbness or tingling in the fingers of the hands and feet, occasionally extending to the rest of the limb
• redness, swelling or blisters in the mouth and/or throat
• pain, swelling, redness or numbness in the hands and/or feet
• shortness of breath
• headache
• cough
• vomiting
• nausea

Common side effects (may affect up to 1 in 10 people):

• allergic reactions
• throat infections
• bladder and skin infections
• sinus inflammation
• liver inflammation
• kidney disorders
• increased muscle tone or tension (hypertonia)
• pain in the arms and/or legs
• itchy skin rash
• drowsiness
• haemorrhoids
• itching
• dry mouth and dry skin
• dry eyes
• sweating
• fatigue and malaise
• anxiety states
• depression
• asthma
• lung infection
• lung disorders
• back pain
• neck pain
• bone pain
• acne
• leg cramps

Uncommon side effects (may affect up to 1 in 100 people):

• deafness
• skin rash with hives
• wheezing
• inflammation or scarring in the lungs (fibrosis)

Rare side effects (may affect up to 1 in 1,000 people):

• jaundice
• anaphylactic reactions

Other side effects that have been reported (frequency cannot be estimated from the available data):

• blood clotting abnormalities or changes
• high potassium levels
• swelling or bleeding in the deep part of the eye
• shock
• abnormal heart rhythm
• respiratory distress
• respiratory failure
• acute accumulation of fluid in the lungs
• acute narrowing of the airways
• abnormally low levels of oxygen in the blood
• difficulty breathing when lying down
• liver damage
• swelling of the face, lips and throat
• kidney failure
• abnormally low levels of fluid around the baby in the womb
• inadequate development of the baby’s lungs in the womb
• abnormal development of the baby’s kidneys in the womb

Some of the side effects that occur may be due to cancer. If you are receiving Tuznue in combination with chemotherapy, some of these side effects may also be due to the chemotherapy.
If you experience any of the side effects, tell your doctor, pharmacist or nurse.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Tuznue

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and on the label of the
vial after "Exp". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Infusion solutions must be used immediately after dilution. Do not use this
medicine if, before administration, you notice particles or any change in colour.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Tuznue contains

• The active substance is trastuzumab. Each vial contains:
  • 150 mg of trastuzumab to be dissolved in 7.2 mL of sterile water for injectable preparations, or
  • 420 mg of trastuzumab to be dissolved in 20.0 mL of sterile water for injectable preparations. The resulting solution contains approximately 21 mg/mL of trastuzumab.
• The other components are L-histidine hydrochloride monohydrate, L-histidine, α,α-trehalose dihydrate, polysorbate 20.

Description of the appearance of Tuznue and package contents
Tuznue is a powder for concentrate for solution for infusion supplied in a glass vial sealed with a rubber stopper containing 150 mg or 420 mg of trastuzumab. The powder is a white to pale yellow pellet.
Each pack contains 1 vial of powder.

Marketing Authorisation Holder
Prestige Biopharma Belgium BVBA
Terhulpensesteenweg 449
3090 Overijse, Belgium

Manufacturer
Kymos Pharma Services, S.L.
Parc Tecnològic del Vallès, Ronda Can Fatjó,
7B, Cerdanyola del Vallès,
08290 Barcelona, Spain
Laboratorio Reig Jofre, S.A.
Gran Capitán, 10, Sant Joan Despí,
08970 Barcelona, Spain

More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.
This leaflet is available in all languages of the European Union/European Economic Area on the website of the European Medicines Agency.

The following information is intended exclusively for healthcare professionals:

Tuznue for intravenous use is supplied in sterile, single-use vials that are preservative-free and pyrogen-free.
To prevent medication administration errors and to ensure that the drug being prepared and administered is Tuznue (trastuzumab) and not another product containing trastuzumab (e.g., trastuzumab emtansine or trastuzumab deruxtecan), it is essential to verify the vial label.
The medicinal product must always be stored in its original closed packaging in the refrigerator at a temperature of 2 °C – 8 °C.
A vial of Tuznue reconstituted aseptically with sterile water for injections (not supplied) remains stable for 48 hours at 2 °C – 8 °C after reconstitution and must not be frozen.
From a microbiological standpoint, the reconstituted solution and the Tuznue infusion solution should be used immediately. The product must not be stored after reconstitution and dilution, unless this has occurred under controlled and validated aseptic conditions. If the product is not used immediately, the duration and storage conditions during use are the responsibility of the user.
Appropriate aseptic techniques must be followed for reconstitution and dilution procedures. Care must be taken to ensure the sterility of the prepared solutions. The medicinal product does not contain antimicrobial preservatives or bacteriostatic agents; therefore, aseptic techniques must be employed.

Aseptic preparation, handling, and storage:
Aseptic handling of the medicinal product must be ensured during infusion preparation. The preparation must:

• be performed by trained personnel in accordance with good manufacturing practices, particularly observing aseptic techniques for the preparation of parenteral medicinal products.
• be carried out within laminar flow cabinets or in biologically safe environments, applying standard precautions for the safe handling of intravenous agents.
• be followed by appropriate storage of the intravenous infusion solution, ensuring maintenance of aseptic conditions.

Tuznue must be handled carefully during the reconstitution process. Excessive foaming caused during reconstitution or agitation of the reconstituted Tuznue solution may lead to issues regarding the amount of Tuznue that can be withdrawn from the vial.

Tuznue 150 mg powder for concentrate for solution for infusion
Follow appropriate aseptic techniques. Each 150 mg vial of Tuznue is reconstituted with 7.2 mL of sterile water for injections (not supplied). Avoid using other solvents for reconstitution. This results in 7.4 mL of solution for single dose, containing approximately 21 mg/mL of trastuzumab. A 4% overfill volume ensures withdrawal of the intended 150 mg dose from the vial.

Tuznue 420 mg powder for concentrate for solution for infusion
Follow appropriate aseptic techniques. Each 420 mg vial of Tuznue is reconstituted with 20 mL of sterile water for injections (not supplied). Avoid using other solvents for reconstitution. This results in 21 mL of solution for single dose, containing approximately 21 mg/mL of trastuzumab. A 4.8% overfill volume ensures withdrawal of the intended 420 mg dose from the vial.

Instructions for reconstitution:

1. Using a sterile syringe, slowly inject the appropriate volume (as indicated above)
   of sterile water for injection (not supplied) into the vial containing Tuznue
   lyophilisate, directing the stream towards the lyophilized material.
2. Gently rotate the vial to facilitate reconstitution. DO NOT SHAKE!
   Slight foaming during reconstitution is not unusual. Allow the vial to stand
   upright for approximately 5 minutes. Once reconstituted, Tuznue appears as a
   clear, particle-free solution, from colourless to pale yellow.

Instructions for aseptic dilution of the reconstituted solution:
Determine the volume of solution required:

• Based on a loading dose of 4 mg of trastuzumab/kg body weight, or a subsequent weekly maintenance dose of 2 mg of trastuzumab/kg body weight:

Body weight (kg) × dose ( 4 mg/kg for loading dose or 2 mg/kg for
Volume (mL) = maintenance dose)
21 (mg/mL, concentration of reconstituted solution)

• Based on a loading dose of 8 mg of trastuzumab/kg body weight, or a subsequent dose of 6 mg of trastuzumab/kg body weight every 3 weeks:

Body weight (kg) × dose ( 8 mg/kg for loading dose or 6 mg/kg for
Volume (mL) = maintenance dose)
21 (mg/mL, concentration of reconstituted solution)

Withdraw the required amount of solution from the vial using a sterile needle and syringe, and
add it to a polypropylene infusion bag containing 250 mL of 0.9% sodium chloride solution.
Do not use glucose-containing solutions. The bag should be gently inverted to mix the solution,
to avoid foaming. Parenteral solutions should be inspected visually for particulate matter or
discoloration prior to administration. Once prepared, the infusion should be administered immediately.
If aseptically diluted, it may be stored for 24 hours at a temperature not exceeding 30 °C.