ZERCEPAC 60 mg POWDER FOR CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Zercepac 60 mg powder for concentrate for solution for infusion

Zercepac 150 mg powder for concentrate for solution for infusion

Zercepac 420 mg powder for concentrate for solution for infusion

trastuzumab

This medicinal product is subject to additional monitoring, which will allow for quick identification of new safety information. You can help by reporting any side effects you may get. The last section of this leaflet includes information on how to report side effects.

Read all of this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Zercepac and what is it used for

Zercepac contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal antibodies recognise specific proteins or antigens. Trastuzumab is designed to bind selectively to an antigen called human epidermal growth factor receptor 2 (HER2). HER2 is found in large quantities on the surface of some cancer cells and stimulates the growth of these cells. When Zercepac binds to HER2, it stops the growth of these cells, causing them to die.

Your doctor may prescribe Zercepac for the treatment of breast or gastric cancer when:

• you have early breast cancer, with high levels of a protein called HER2.
• you have metastatic breast cancer (breast cancer that has spread from the original tumour) with high levels of HER2. Zercepac may be prescribed in combination with chemotherapy medicines paclitaxel or docetaxel as first treatment for metastatic breast cancer or it may be prescribed alone if other treatments have not been successful. It is also used in combination with other medicines called aromatase inhibitors in patients with high levels of HER2 and positive hormone receptor for metastatic breast cancer (cancer that is sensitive to female sex hormones).
• you have metastatic gastric cancer with high levels of HER2, and it is used in combination with other cancer medicines such as capecitabine or 5-fluorouracil and cisplatin.

2. What you need to know before you use Zercepac

Do not use Zercepac:

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

Warnings and precautions

Your doctor will closely monitor your treatment.

Cardiac monitoring

Treatment with Zercepac alone or in combination with a taxane may affect the heart, especially if you have received an anthracycline (taxanes and anthracyclines are two types of medicines used to treat cancer) in the past. The effects can be moderate to severe and can be fatal. Therefore, you will need to have your heart function checked before, during (every 3 months) and after (for up to 2 to 5 years) treatment with Zercepac. If you develop any signs of heart failure (the heart not pumping enough blood), your heart function will be checked more frequently (every 6 to 8 weeks), you may receive treatment for heart failure or you may need to stop treatment with Zercepac.

Talk to your doctor, pharmacist or nurse before Zercepac is given to you if:

• you have had heart failure, coronary artery disease, heart valve disease (heart murmur) or high blood pressure, have taken any medicine for high blood pressure or are currently taking any medicine for high blood pressure.
• you have received or are currently receiving a medicine called doxorubicin or epirubicin (medicines for treating cancer). These medicines (or any other anthracycline) can damage the heart muscle and increase the risk of having heart problems when treated with Zercepac.
• you feel short of breath, especially if you are currently receiving a taxane. Zercepac can cause difficulty breathing, especially when given for the first time. This could be more severe if you already have shortness of breath. In very rare cases, patients with severe breathing difficulties before treatment have died when given Zercepac.
• you have had any other cancer treatment in the past.

If you receive Zercepac with any other medicine for cancer, such as paclitaxel, docetaxel, an aromatase inhibitor, capecitabine, 5-fluorouracil or cisplatin, you should also read the package leaflets for these medicines.

Children and adolescents

Zercepac is not recommended for children under 18 years of age.

Other medicines and Zercepac

Using Zercepac with other medicines: Tell your doctor, pharmacist or nurse if you are using, have recently used or might use any other medicines.

It may take up to 7 months for Zercepac to be completely eliminated from the body. Therefore, if you are going to take any new medicine within the next 7 months after stopping treatment, you should tell your doctor, pharmacist or nurse that you have been treated with Zercepac.

Pregnancy

• If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before using this medicine.
• You must use an effective method of contraception during treatment with Zercepac and for at least 7 months after stopping treatment.
• Your doctor will discuss the risks and benefits of taking Zercepac during pregnancy. In rare cases, a decrease in the fluid that surrounds the developing baby in the womb (amniotic fluid) has been observed in pregnant women given Zercepac. This can be harmful to the baby in the womb and has been associated with underdeveloped lungs, resulting in fetal death.

Breast-feeding

You must not breast-feed your baby during therapy with Zercepac and for 7 months after the last dose of Zercepac, as Zercepac may pass into your breast milk.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Zercepac may affect your ability to drive or use machines. If you experience symptoms during treatment, such as dizziness, drowsiness, chills or fever, do not drive or use machinery until these symptoms have disappeared.

Sodium

This medicine contains less than 1 mmol of sodium (23 mg) per dose; this is “essentially sodium-free”.

3. How to use Zercepac

Before starting treatment with Zercepac, your doctor will determine the amount of HER2 in your tumour. Only patients with a high amount of HER2 will be treated with Zercepac. Zercepac must be administered only by a doctor or nurse. Your doctor will prescribe a dose and treatment schedule suitable for you. The dose of Zercepac depends on your body weight.

The intravenous formulation of Zercepac is administered as an intravenous infusion (“drip”) directly into a vein. The first dose of your treatment is administered over approximately 90 minutes and you will be observed by a healthcare professional while it is being given, in case you have any adverse reactions. If the initial dose has been well tolerated, subsequent doses may be administered over 30 minutes (see section 2 “Warnings and precautions”). The number of infusions you may receive will depend 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 Zercepac (trastuzumab) and not another product containing trastuzumab (e.g. trastuzumab emtansine or trastuzumab deruxtecan).

For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Zercepac will be administered every 3 weeks. Zercepac may also be administered once a week for metastatic breast cancer.

If you stop treatment with Zercepac

Do not stop treatment with this medicine without talking to your doctor first. All doses should be taken at the right time every week or every 3 weeks (depending on your dosing schedule). This helps your medicine work properly.

It may take up to 7 months for Zercepac to be completely eliminated from the body. Therefore, your doctor may decide to continue checking your heart function even after you have finished treatment.

If you have any other questions about the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, Zercepac can cause side effects, although not everybody gets them. Some of these side effects can be serious and may require hospitalisation.

Serious side effects

During administration of a Zercepac infusion, you may experience chills, fever and other flu-like symptoms. This is very common (affects more than 1 in 10 people). Other infusion-related symptoms are: feeling sick (nausea), vomiting, pain, increased muscle tension and agitation, headache, dizziness, difficulty breathing, decreased or increased blood pressure, changes in heart rhythm (palpitations, arrhythmias or irregular heartbeat), swelling of the face and lips, rash and feeling tired. Some of these symptoms can be serious and some patients have died (see section 2 “Warnings and precautions”).

These effects usually occur during the first intravenous infusion (“drip” into a vein) and during the first few hours after the start of the infusion. They are usually temporary. A healthcare professional will monitor you during the infusion and for at least 6 hours after the start of the first infusion and for 2 hours after the start of subsequent infusions. If you have any reaction, the infusion may be given more slowly or the infusion may be stopped and you may be given treatment to counteract the side effects. The infusion can continue once your symptoms have improved.

Occasionally, symptoms start after 6 hours after the start of the infusion. If this happens to you, contact your doctor immediately. Sometimes, the symptoms may improve and then worsen later.

Other serious side effects may occur at any time during treatment with Zercepac and not just related to the infusion. Tell your doctor or nurse if you experience any of the following side effects:

• Heart problems can occur during treatment and occasionally after stopping treatment, and these can be serious. These include weakening of the heart muscle that can lead to heart failure, inflammation of the layer surrounding the heart (swelling, redness, heat and pain) and changes in heart rhythm. This can cause symptoms such as shortness of breath (even when lying down), cough, fluid retention (swelling) of the legs or arms, palpitations (arrhythmias or irregular heartbeat) (see section 2. Cardiac monitoring).

Your doctor will regularly check your heart during and after treatment, but you should tell your doctor immediately if you notice any of the symptoms mentioned above.

• Tumour lysis syndrome (a group of metabolic complications that occur after cancer treatment and are 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 (palpitations, faster or slower heart rate). Seizures, vomiting or diarrhoea and tingling in the mouth, hands or feet.

If you experience any of these symptoms after your treatment with Zercepac has finished, you should contact your doctor and inform them that you have been previously treated with Zercepac.

Other side effects

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

• infections
• diarrhoea
• constipation
• heartburn (dyspepsia)
• fatigue
• skin rash (hives)
• chest pain
• abdominal pain
• joint pain
• low count of red and white blood cells (which help fight infection) sometimes with fever
• muscle pain
• conjunctivitis
• tear production
• nasal bleeding
• nasal discharge
• hair loss
• tremor
• hot flushes
• dizziness
• nail changes
• weight loss
• loss of appetite
• difficulty sleeping (insomnia)
• taste changes
• low platelet count
• bruising
• numbness or tingling in the fingers of the hands and feet, which may occasionally spread to the rest of the limb
• redness, swelling or ulcers in the mouth and/or throat
• pain, swelling, redness or tingling in the hands and/or feet
• difficulty breathing
• headache
• cough
• vomiting
• nausea

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

• allergic reactions
• throat infections
• bladder and skin infections
• breast inflammation
• liver inflammation
• kidney disorders
• increased muscle tone (hypertonia)
• pain in the arms and/or legs
• itchy skin rash
• feeling sleepy (somnolence)
• haemorrhoids
• itching
• dry mouth and skin
• dry eyes
• sweating
• feeling weak and unwell
• anxiety
• depression
• asthma
• lung infection
• lung changes
• back pain
• neck pain
• bone pain
• acne
• leg cramps

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

• hearing loss
• skin rash with blisters
• wheezing (whistling sound while breathing)
• inflammation/scarring of the lungs

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

• jaundice
• anaphylactic reactions

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

• abnormal blood clotting or clotting problems
• high levels of potassium
• inflammation or bleeding in the back of the eyes
• shock
• abnormal heart rhythm
• difficulty breathing
• respiratory failure
• fluid build-up in the lungs
• narrowing of the airways
• abnormally low levels of oxygen in the blood
• difficulty breathing while lying down
• liver damage
• inflammation of the face, lips and throat
• kidney failure
• abnormally low levels of fluid surrounding the baby in the womb
• failure of the baby’s lungs to develop in the womb
• abnormal development of the baby’s kidneys in the womb

Some of the side effects you may have may be due to your cancer. If you are given Zercepac in combination with chemotherapy, some of the side effects may also be due to the chemotherapy itself.

If you experience any side effects, tell your doctor, pharmacist or nurse.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Zercepac

Zercepac will be stored by healthcare professionals in the hospital or clinic.

• 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 is the last day of the month shown.
• Unopened vials should be stored in a refrigerator (between 2°C and 8°C).
• Do not freeze the reconstituted solution.
• Infusion solutions should be used immediately after dilution. If not used immediately, the storage time before use and storage conditions are the responsibility of the user.
• Do not use Zercepac if you notice any foreign particles or discolouration before administration.
• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Container Content and Additional Information

Zercepac Composition

• The active ingredient is trastuzumab. Each vial contains either
• 60 mg of trastuzumab that dissolves in 3.0 ml of sterile water for injectable preparations, or
• 150 mg of trastuzumab that dissolves in 7.2 ml of sterile water for injectable preparations, or
• 420 mg of trastuzumab that dissolves 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, alpha, alpha-trehalose dihydrate, polysorbate 20.

Product Appearance and Container Content

Zercepac is a powder for concentrate for solution for intravenous infusion, presented in a glass vial with a rubber stopper containing 60 mg, 150 mg, or 420 mg of trastuzumab. It is a lyophilized powder in a white to pale yellow pellet. Each container 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

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

Date of Last Revision of this Leaflet:

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/

On the European Medicines Agency website, this leaflet can be found in all languages of the European Union/European Economic Area.

This information is intended for healthcare professionals only:

Zercepac IV is provided in sterile, preservative-free, non-pyrogenic, single-use vials.

To avoid medication errors, it is essential to check the labels of the vials to ensure that the medication being prepared and administered is Zercepac (trastuzumab) and not another product containing trastuzumab (e.g., trastuzumab emtansine or trastuzumab deruxtecan).

Always keep this medication in its original closed container at a temperature of 2 °C-8 °C in the refrigerator.

Since the medication does not contain antimicrobial preservatives or bacteriostatic agents, appropriate aseptic technique should be used for reconstitution and dilution procedures. Care should be taken to ensure the sterility of the prepared solutions.

The vial of Zercepac reconstituted aseptically with sterile water for injectable preparations (not supplied) is chemically and physically stable for 48 hours at 2 °C-8 °C after reconstitution and should not be frozen.

After aseptic dilution in polyethylene or polypropylene bags containing 9 mg/ml (0.9%) sodium chloride solution, the physical and chemical stability of Zercepac has been demonstrated for a period of up to 84 days at 2 °C to 8 °C, 7 days at 23 °C to 27 °C, and 24 hours at 30 °C.

From a microbiological point of view, the reconstituted solution and the infusion solution of Zercepac should be used immediately. If not used immediately, the storage time until use and the storage conditions before use will be the responsibility of the user, unless the reconstitution and dilution take place under controlled and validated aseptic conditions.

Storage, handling, and aseptic preparation:

The preparation of the infusion should be:

• developed by qualified personnel according to good practices, especially regarding the aseptic preparation of parenteral products.
• prepared in a laminar flow cabinet or biological safety cabinet using usual precautions for the safe handling of intravenous agents.
• followed by adequate storage of the prepared infusion solution
• for intravenous infusion to ensure the maintenance of aseptic conditions.

Instructions for aseptic reconstitution:

1. Using a sterile syringe, slowly inject the corresponding volume (as indicated below) of sterile water for injectable preparations (not supplied) into the vial containing the lyophilized Zercepac, directing the flow towards the lyophilized material. The use of other solvents for reconstitution should be avoided.
2. Gently move in circles to aid reconstitution. DO NOT SHAKE!

The formation of a slight foam after reconstitution is usual. Let the vial stand for approximately 5 minutes. The reconstituted Zercepac is a clear, colorless to pale yellow solution and should be essentially free of 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 injection produces a 3.1 ml solution for single dose that contains 21 mg/ml of trastuzumab, at a pH of approximately 6.0. An overfill of 8% allows the dose of 60 mg stated on the label to be withdrawn from each 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 injection produces a 7.5 ml solution for single dose that contains 21 mg/ml of trastuzumab, at a pH of approximately 6.0. An overfill of 5% allows the dose of 150 mg stated on the label to be withdrawn from each 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 injection produces a 20.6 ml solution for single dose that contains approximately 21 mg/ml of trastuzumab, at a pH of approximately 6.0. An overfill of 3% allows the dose of 420 mg stated on the label to be withdrawn from each vial.

Zercepac should be handled carefully during reconstitution. If excessive foam is produced during reconstitution or the reconstituted Zercepac is shaken, it may cause problems with the amount of Zercepac that can be withdrawn from the vial.

Instructions for aseptic dilution of the reconstituted solution

The required volume of solution will be determined:

• based on the initial dose of 4 mg of trastuzumab/kg of body weight or subsequent weekly doses of 2 mg of trastuzumab/kg of body weight:

Volume(ml) = Body Weight(kg) x Dose(4mg/kg initial dose or 2mg/kg for subsequent doses)

21(mg/ml, concentration of the reconstituted solution)

The required volume of solution will be determined based on the initial dose of 8 mg of trastuzumab/kg of body weight or doses every three weeks of 6 mg of trastuzumab/kg of body weight

Volume(ml) = Body Weight(kg) x Dose(8mg/kg initial dose or 6mg/kg for subsequent doses)

21(mg/ml, concentration of the reconstituted solution)

The appropriate amount of solution should be withdrawn from the vial using a sterile needle and syringe and added to a polyethylene or polypropylene infusion bag containing 250 ml of 9 mg/ml (0.9%) sodium chloride solution. It should not be used with solutions containing glucose. The bag should be inverted several times to mix the solution and avoid foam formation. Parenteral solutions should be visually inspected for particles and discoloration before administration.