HERZUMA 150 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Herzuma 150mg 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 Herzuma is and what it is used for
2. What you need to know before you use Herzuma
3. How to use Herzuma
4. Possible side effects
5. Storage of Herzuma
6. Contents of the pack and other information

1. What Herzuma is and what it is used for

Herzuma 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 Herzuma binds to HER2, it stops the growth of these cells, leading to their death.

Your doctor may prescribe Herzuma 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) with high levels of HER2. Herzuma may be prescribed in combination with chemotherapy medicines paclitaxel or docetaxel as a 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 Herzuma

Do not use Herzuma:

? if you are allergic to trastuzumab, to murine proteins (from mice) or to any of the other ingredients of this medicine (listed in section 6).

? if you have severe respiratory problems at rest due to your tumour or if you need oxygen treatment.

Warnings and precautions

Talk to your doctor or nurse before starting treatment with Herzuma.

Your doctor will closely monitor your treatment.

Cardiac monitoring

Treatment with Herzuma alone or in combination with a taxane may affect the heart, especially if you have previously received an anthracycline (taxanes and anthracyclines are two types of medicines used to treat cancer). 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 Herzuma. 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 Herzuma.

Talk to your doctor, pharmacist or nurse before you are given Herzuma 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 previously 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 heart problems when treated with trastuzumab.

? you feel short of breath, especially if you are currently receiving a taxane. Trastuzumab can cause difficulty breathing, especially when given for the first time. This could be more serious if you already have shortness of breath. In very rare cases, patients with severe breathing difficulties before treatment have died when given trastuzumab.

? you have had any other cancer treatment.

If you receive Herzuma 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 leaflets for these medicines.

Children and adolescents

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

Other medicines and Herzuma

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

Pregnancy and breastfeeding

? 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 Herzuma and for at least 7 months after finishing treatment.

? Your doctor will discuss the risks and benefits of taking Herzuma during pregnancy. In rare cases, a decrease in the fluid that surrounds the developing baby in the womb (amniotic fluid) has been seen in pregnant women given Herzuma. This can be harmful to the baby and has been associated with underdeveloped lungs and death of the fetus.

Breastfeeding

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

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

Driving and using machines

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

Sodium

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

3. How to use Herzuma

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

Herzuma is given as an intravenous infusion (a drip) directly into a vein. The first dose of your treatment is given over about 90 minutes and you will be observed by a healthcare professional while it is being given, in case you have any side effects. If the initial dose is well tolerated, subsequent doses may be given over 30 minutes (see section 2 “Warnings and precautions”). The number of infusions you can 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 given is Herzuma (trastuzumab) and not trastuzumab emtansine.

For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Herzuma will be given every 3 weeks. Herzuma can also be given once a week for metastatic breast cancer.

If you stop treatment with Herzuma

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 Herzuma to be eliminated from your body. Therefore, your doctor may decide to continue monitoring your heart function even after you finish treatment.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these side effects can be serious and may need hospital treatment.

During the infusion of Herzuma, 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 include: feeling sick (nausea), vomiting, pain, increased muscle tension and agitation, headache, dizziness, difficulty breathing, wheezing (piping), low or high blood pressure, irregular heartbeat (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 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 a reaction, the infusion may be given more slowly or stopped and you may be given treatment to counteract the side effects. The infusion can continue once your symptoms have improved.

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

Serious side effects

Other side effects may occur at any time during treatment with Herzuma 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 effects include weakening of the heart muscle that can lead to heart failure, inflammation of the layer surrounding the heart and irregular heartbeat. 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 set of metabolic complications that occur after cancer treatment, characterised by high levels of potassium and phosphate in the blood and low levels of calcium in the blood). Symptoms can include kidney problems (weakness, shortness of breath, fatigue and confusion), heart problems (heart palpitations or a faster or slower heartbeat). Seizures, vomiting or diarrhoea and tingling in the mouth, hands or feet.

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

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

? infections

? diarrhoea

? constipation

? heartburn (dyspepsia)

? fatigue

? skin rash

? chest pain

? abdominal pain

? joint pain

? low red blood cell and white blood cell counts (which help fight infection) sometimes with fever

? muscle pain

? conjunctivitis

? tearing

? nosebleeds

? nasal discharge

? hair loss

? tremors

? 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 and toes

? 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):

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

? deafness

? blistering skin rash

? wheezing (piping)

? lung inflammation/scarring

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

? jaundice

? anaphylactic reactions

Other side effects reported with the use of Herzuma(frequency cannot be estimated from the available data):

? abnormal blood clotting or bleeding

? high levels of potassium

? inflammation or bleeding in the back of the eyes

? shock

? abnormal heartbeat

? difficulty breathing

? respiratory failure

? sudden accumulation of fluid in the lungs

? sudden narrowing of the airways

? abnormally low levels of oxygen in the blood

? difficulty breathing when 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 experience may be due to your cancer. If you are given Herzuma in combination with chemotherapy, some of the side effects may also be due to the chemotherapy itself.

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

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist or nurse, even if they are 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 Herzuma

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 the month shown.

Store in a refrigerator (2°C to 8°C).

Infusion solutions should be used immediately after dilution. Do not use this medicine if you notice any 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. These measures will help protect the environment.

6. Container contents and additional information

Herzuma composition

The active substance is trastuzumab. Each vial contains 150 mg of trastuzumab, which is dissolved in 7.2 ml of water for injectable preparations. The resulting solution contains approximately 21 mg/ml of trastuzumab.

The other components are L-histidine hydrochloride, L-histidine, α,α-trehalose dihydrate, polysorbate 20.

Appearance of the product and container contents

Herzuma is a powder for concentrate for solution for intravenous infusion, which is presented in a glass vial with a rubber stopper containing 150 mg of trastuzumab. It is a white to pale yellow lyophilized pellet. Each box contains 1 vial of powder.

Marketing authorization holder

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Manufacturer

Millmount Healthcare Ltd.

Block 7

City North Business Campus

Stamullen, Co. Meath K32 YD60

Ireland

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of last revision of this leaflet:<{MM/AAAA}>.

Other sources of information

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

This leaflet can be found in all languages of the European Union/European Economic Area on the European Medicines Agency website.

This information is intended for healthcare professionals only

Always keep this medicine in its original closed container at a temperature between 2°C and 8°C in the refrigerator.

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

The Herzuma vial reconstituted aseptically with sterile water for injectable preparations (not supplied) is chemically and physically stable for 7 days at 2°C to 8°C after reconstitution and should not be frozen.

After aseptic dilution in polyvinyl chloride, polyethylene, or polypropylene bags containing 9 mg/ml (0.9%) sodium chloride injection solution, the physical and chemical stability of Herzuma has been demonstrated for up to 30 days at 2°C to 8°C and 24 hours at a temperature not exceeding 30°C.

From a microbiological point of view, the reconstituted solution and the infusion solution of Herzuma should be used immediately. If not used immediately, the storage time before use and the storage conditions will be the responsibility of the user and, in general, should not exceed 24 hours at 2°C to 8°C, unless the reconstitution and dilution are performed under controlled and validated aseptic conditions.

Aseptic handling and preparation

Aseptic handling should be ensured when preparing the infusion. The preparation should be:

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

Each vial of Herzuma is reconstituted with 7.2 ml of sterile water for injectable preparations (not supplied). The use of other solvents for reconstitution should be avoided. This produces a single-dose solution of 7.4 ml, which contains approximately 21 mg/ml of trastuzumab. A 4% overfill allows the labeled dose of 150 mg to be withdrawn from each vial.

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

Instructions for aseptic reconstitution:

1. Using a sterile syringe, slowly inject 7.2 ml of sterile water for injectable preparations into the vial containing the Herzuma lyophilized powder, directing the stream towards the lyophilized powder.
2. Gently swirl in a circular motion to aid in dissolution. DO NOT SHAKE!

The formation of a slight foam after reconstitution is normal. Allow the vial to stand for approximately 5 minutes. The reconstituted Herzuma is a clear, colorless to pale yellow solution and should be essentially free of visible particles.

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)

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 and added to a polyvinyl chloride, polyethylene, or polypropylene infusion bag containing 250 ml of 0.9% sodium chloride injection solution. Do not use 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.