Zercepac

Package leaflet: Information for the user

Zercepac 60 mg powder for concentrate for solution for infusion, 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 all of 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 or pharmacist.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

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

1. What Zercepac is and what it is used for

Zercepac 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 tumour cells and stimulates their growth. When Zercepac binds to HER2, it blocks the growth of these cells and causes their death.

Your doctor may prescribe Zercepac 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 tumour) with high levels of HER2. Zercepac may be prescribed in combination with the chemotherapy 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 hormone receptor-positive metastatic breast cancer (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 Zercepac

Do not use Zercepac if:

• you are allergic to trastuzumab, murine proteins (mouse 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 therapy.

Warnings and precautions
Your doctor will closely monitor you during treatment.
Heart checks
Treatment with Zercepac, either 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 tumours). These effects may range from moderate to severe and can be fatal. Your heart function will therefore be checked before, during (every three months), and after (up to two to five years) treatment with Zercepac. If you develop signs of heart failure (i.e. the heart's inability to pump blood adequately), you may require more frequent heart function monitoring (every six to eight weeks), may need treatment for heart failure, or may have to stop treatment with Zercepac.
Talk to your doctor, pharmacist, or nurse before receiving Zercepac 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 tumours). These medicines (or any other anthracycline) can damage heart muscle and increase the risk of heart problems when taking Zercepac;
• you suffer from shortness of breath, especially if you are currently receiving a taxane. Zercepac can cause difficulty breathing, particularly 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 Zercepac;
• you have received other cancer treatments.

If you are receiving Zercepac 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 for those medicines.
Children and adolescents
Zercepac is not recommended for patients under 18 years of age.
Other medicines and Zercepac
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 Zercepac to be eliminated from the body. Therefore, inform your doctor, pharmacist, or nurse that you have been given Zercepac 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 Zercepac and for at least 7 months after the end of treatment.
• Your doctor will discuss with you the risks and benefits of taking Zercepac during pregnancy. In rare cases, women treated with Zercepac during pregnancy have experienced reduced amniotic fluid surrounding the developing baby in the womb. This condition may be harmful to the unborn baby and has been associated with incomplete lung development, leading to fetal death.

Breast-feeding
Do not breast-feed during treatment with Zercepac and for 7 months after the last dose of Zercepac, as Zercepac may pass into breast milk and harm the baby.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Zercepac may affect your ability to drive or use machinery. If you develop symptoms such as dizziness, drowsiness, chills, or fever during treatment, do not drive or operate machinery until these symptoms have resolved.
Sodium
Zercepac contains less than 1 mmol of sodium per dose, i.e., essentially "sodium-free".

3. How Zercepac 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 Zercepac. Zercepac must be administered only
by a doctor or nurse. Your doctor will prescribe the dose and treatment schedule appropriate for you.
The dose of Zercepac depends on your body weight.
The intravenous formulation of Zercepac is given as an intravenous infusion (“drip”) directly into the
veins. The first dose is administered over a period of 90 minutes, and you will be monitored by a
healthcare professional during administration in case you experience any adverse effects. If the first
dose is well tolerated, subsequent doses may be administered over a period of 30 minutes (see
section 2 “Warnings and precautions”). The number of infusions you will receive depends on your
response to treatment. Your doctor will discuss this with you.
To prevent medication errors, it is important to check the vial labels to ensure that the medicine being
prepared and administered is Zercepac (trastuzumab) and not another trastuzumab-based medicine (e.g.
trastuzumab emtansine or trastuzumab deruxtecan).
In patients with early-stage breast cancer, metastatic breast cancer, and metastatic gastric cancer,
Zercepac is administered every 3 weeks. Zercepac may also be administered once weekly for the
treatment of metastatic breast cancer.
If you interrupt treatment with Zercepac
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 Zercepac 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 doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Zercepac can cause side effects, although not everyone gets them. Some of these side effects can be serious and may require hospitalisation.
Serious side effects
During infusion of Zercepac, 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 tone 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 tired. Some of these symptoms may 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 infusion. They are generally 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 infusion. If this happens, contact your doctor immediately. Sometimes symptoms may improve initially but worsen later.
Other serious side effects may occur at any time during treatment with Zercepac, not only in relation to an infusion. Contact your doctor or nurse immediately if you notice any of the following side effects:

• Heart problems that may be potentially serious can sometimes occur during treatment and, occasionally, after treatment has been stopped. These include weakening of the heart muscle which may lead to heart failure, inflammation (swelling, redness, warmth and pain) of the lining of the heart, and heart rhythm disturbances. These may cause symptoms such as shortness of breath (including at night), cough, fluid retention (swelling) in the legs or arms, and palpitations (fast 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 described 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 (fast or slow heartbeat), seizures, vomiting or diarrhoea, and tingling around the mouth, hands or feet.

If you experience any of the symptoms described above after completing treatment with Zercepac, contact your doctor and inform them about your previous treatment with Zercepac.
Other side effects
Very common side effects of Zercepac: may affect more than 1 in 10 people

• infections
• diarrhoea
• constipation
• heartburn (dyspepsia)
• fatigue
• skin rashes
• chest pain
• abdominal pain
• joint pain
• low red blood cell 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 fingers and toes, which may occasionally extend 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 arms and/or legs
• itchy skin rash
• drowsiness
• haemorrhoids
• itching
• dry mouth and dry skin
• dry eyes
• sweating
• fatigue and malaise
• anxiety
• 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 wheals
• wheezing
• inflammation or scarring in the lungs (fibrosis)

Rare side effects: may affect up to 1 in 1000 people:

• jaundice
• anaphylactic reactions

Other side effects with unknown frequency: the frequency cannot be estimated from the available data:

• blood clotting abnormalities or alterations
• high levels of potassium
• 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 amniotic fluid surrounding the unborn child
• inadequate development of the unborn child’s lungs
• abnormal development of the unborn child’s kidneys

Some of the side effects that occur may be due to the cancer itself. If you are receiving Zercepac in combination with chemotherapy, some of these side effects may also be due to the chemotherapy.
If you experience any side effect, inform your doctor, pharmacist or nurse.
Reporting of side effects
If you get any side effect, including ones 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.
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Zercepac

Zercepac must be stored by healthcare personnel at the hospital or clinic.

• 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 after "Exp./EXP". The expiry date refers to the last day of that month.
• Store the vial in the refrigerator (2 °C - 8 °C) prior to opening.
• Do not freeze the reconstituted solution.
• Infusion solutions should be used immediately after dilution. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user.
• Do not use Zercepac if you notice any particles or change in colour before administration.
• Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Zercepac contains

• The active substance is trastuzumab. Each vial contains:
  • 60 mg of trastuzumab to be dissolved in 3.0 ml of sterile water for injections, or
  • 150 mg of trastuzumab to be dissolved in 7.2 ml of sterile water for injections, or
  • 420 mg of trastuzumab to be dissolved in 20.0 ml of sterile water for injections.
• The resulting solution contains approximately 21 mg/ml of trastuzumab.
• The other ingredients are L-histidine hydrochloride monohydrate, L-histidine, α,α-trehalose dihydrate, polysorbate 20.

Description of the appearance of Zercepac and contents of the pack
Zercepac is a powder for concentrate for solution for intravenous infusion supplied in a
glass vial sealed with a rubber stopper containing 60 mg, 150 mg, or 420 mg of trastuzumab.
The powder is a white to pale yellow pellet. Each pack contains 1 vial of powder.

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

Manufacturer
Accord Healthcare Polska Sp. z.o.o
ul Lutomierska 50, 95-200 Pabianice
Poland

For further information on this medicinal product, please contact the local representative of the Marketing Authorization Holder:
AT / BE / BG / CY / CZ / DE / DK / EE / FI / FR / HR / HU / IE / IS / IT / LT / LV / LU / MT / NL / NO / PT / PL / RO / SE / SI / SK / ES
Accord Healthcare S.L.U.
Tel: +34 93 301 00 64
EL Win Medica A.E.
Tel: +30 210 7488 821

More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://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 physicians or healthcare professionals

Zercepac 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 Zercepac (trastuzumab) and not another trastuzumab-containing product (e.g., trastuzumab emtansine or trastuzumab deruxtecan), it is essential to check the vial label.
Always store the medicinal product in its original closed packaging at 2 °C – 8 °C in a refrigerator.
The medicinal product does not contain antimicrobial preservatives or bacteriostatic agents; therefore, aseptic techniques must be used during reconstitution and dilution procedures. Care must be taken to ensure sterility of the prepared solutions.
A vial of Zercepac reconstituted aseptically with sterile water for injections (not supplied) remains chemically and physically stable for 48 hours at 2 °C – 8 °C after reconstitution and must not be frozen.
After aseptic dilution into polyethylene or polypropylene infusion bags containing 9 mg/ml (0.9%) sodium chloride injection solution, the chemical and physical stability of Zercepac has been demonstrated for up to 84 days at 2 °C – 8 °C, 7 days at 23 °C – 27 °C, and 24 hours at 30 °C.
From a microbiological standpoint, the reconstituted solution and the infusion solution of Zercepac should be used immediately. If not used immediately, the storage period and conditions prior to and during use are the responsibility of the user, unless the dilution was performed under controlled and validated aseptic conditions.

Aseptic preparation, handling, and storage:
The preparation of the infusion must:

• be carried out by trained personnel in accordance with good manufacturing practices, particularly observing aseptic techniques for the preparation of parenteral medicinal products;
• be performed within laminar flow hoods 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.

Instructions for aseptic reconstitution:

1. Using a sterile syringe, slowly inject the appropriate volume (as indicated below) of sterile water for injections (not supplied) into the vial containing the lyophilized Zercepac, directing the stream onto the lyophilized material. Do not use other solvents for reconstitution;
2. Gently rotate the vial to facilitate reconstitution. DO NOT SHAKE!
   Slight foaming during reconstitution is not unusual. Allow the vial to stand vertically for approximately 5 minutes. Once reconstituted, Zercepac appears as a clear, colorless to pale yellow solution, free from visible particles.

Zercepac 60 mg powder for concentrate for solution for infusion
Reconstitution of the 60 mg vial with 3.0 ml of sterile water for injections yields 3.1 ml of solution for single dose, containing approximately 21 mg/ml of trastuzumab, with a pH of approximately 6.0. An overfill of 8% ensures withdrawal of the intended 60 mg dose from the vial.

Zercepac 150 mg powder for concentrate for solution for infusion
Reconstitution of the 150 mg vial with 7.2 ml of sterile water for injections yields 7.5 ml of solution for single dose, containing approximately 21 mg/ml of trastuzumab, with a pH of approximately 6.0. An overfill of 5% ensures withdrawal of the intended 150 mg dose from the vial.

Zercepac 420 mg powder for concentrate for solution for infusion
Reconstitution of the 420 mg vial with 20.0 ml of sterile water for injections yields 20.6 ml of solution for single dose, containing approximately 21 mg/ml of trastuzumab, with a pH of approximately 6.0. An overfill of 3% ensures withdrawal of the intended 420 mg dose from the vial.

Zercepac must be handled carefully during the reconstitution process. Excessive foaming during reconstitution or agitation of the reconstituted Zercepac solution may lead to difficulties in withdrawing the intended amount of Zercepac from the vial.

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

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

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

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

Volume (ml) = body weight (kg) × dose ( 8 mg/kg for loading dose or 6 mg/kg for maintenance dose)
21 (mg/ml, concentration of reconstituted solution)
Withdraw the required volume of solution from the vial using a sterile needle and syringe and add it to a polyethylene or polypropylene infusion bag containing 250 ml of 9 mg/ml (0.9%) sodium chloride solution. Do not use glucose-containing solutions. The bag should be gently inverted to mix the solution, avoiding foaming. Parenteral solutions should be visually inspected for particulate matter and discoloration prior to administration.