ONTRUZANT 420 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Ontruzant 150 mg powder for concentrate for solution for infusion

Ontruzant 420 mg powder for concentrate for solution for infusion

trastuzumab

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

1. What is Ontruzant and what is it used for

Ontruzant contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal antibodies attach to specific proteins or antigens. Trastuzumab is designed to attach itself 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, stimulating their growth. When Ontruzant attaches to HER2, it stops the growth of these cells and causes them to die.

Your doctor may prescribe Ontruzant for the treatment of breast or gastric cancer if:

• you have early breast cancer with high levels of the HER2 protein;
• you have metastatic breast cancer (breast cancer that has spread beyond the original tumor) with high levels of HER2. Ontruzant 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 the presence of female sex hormones);
• you have metastatic gastric cancer with high levels of HER2, when combined with other cancer medicines such as capecitabine or 5-fluorouracil and cisplatin.

2. What you need to know before you use Ontruzant

Do not use Ontruzant

• 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 cancer or if you need oxygen treatment.

Warnings and precautions

Your doctor will closely monitor your treatment.

Heart checks

Treatment with Ontruzant (alone or with a taxane) may affect the heart, especially if you have ever used an anthracycline (taxanes and anthracyclines are two other classes of medicines used to treat cancer).

The effects can be moderate to severe and may be fatal. Therefore, your heart function will be checked before, during (every three months) and after (two to five years) treatment with Ontruzant. If you show signs of heart failure (inadequate blood pumping from your heart), your heart function may be checked more frequently (every six to eight weeks), you may receive treatment for heart failure, or you may need to stop treatment with Ontruzant.

Talk to your doctor, pharmacist, or nurse before you are given Ontruzant if:

• you have had heart failure, coronary artery disease, heart valve disease (heart murmur), high blood pressure, are currently taking or have taken any medicine for high blood pressure;

• you are currently taking or have ever taken a medicine called doxorubicin or epirubicin (medicines used to treat cancer). These medicines (or any other anthracycline) can damage the heart muscle and increase the risk of heart problems with Ontruzant;

• you feel short of breath, especially if you are currently using a taxane. Ontruzant can cause breathing difficulties, especially when administered for the first time. Breathing difficulties may be more severe if you already have difficulty breathing. In very rare cases, patients who already had breathing difficulties before treatment have died after receiving Ontruzant;

• you have ever had any other cancer treatment.

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

Children and adolescents

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

Other medicines and Ontruzant

Using Ontruzant with other medicines: Tell 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 Ontruzant to be eliminated from the body. Therefore, if you are going to take a new medicine in the 7 months following the end of treatment, inform your doctor, pharmacist, or nurse that you have received treatment with Ontruzant.

Pregnancy and breast-feeding

• If you are pregnant, think you may be pregnant, or plan to become pregnant, consult your doctor, pharmacist, or nurse before using this medicine.
• You must use effective contraceptive methods during treatment with Ontruzant and for at least 7 months after the end of treatment.
• Your doctor will explain the risks and benefits of using Ontruzant during pregnancy. In rare cases, a decrease in the fluid (amniotic fluid) surrounding the developing fetus in the womb has been observed in pregnant women treated with Ontruzant. This condition can be harmful to the fetus in the womb and has been associated with a problem of complete development of the lungs leading to fetal death.

Breast-feeding

Do not breast-feed your child during treatment with Ontruzant and for 7 months after the last dose, as Ontruzant may pass into your child through breast milk.

Consult your doctor or pharmacist before using this medicine.

Driving and using machines

Ontruzant may affect your ability to drive a vehicle or operate machinery. If you experience symptoms during treatment such as dizziness, drowsiness, chills, or fever, do not drive or use machinery until these symptoms disappear.

Sodium

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

3. How to use Ontruzant

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

Ontruzant is administered as an infusion into a vein (intravenous infusion, "drip"). This intravenous formulation must not be administered subcutaneously and must only be administered as an intravenous infusion.

The first dose of your treatment is administered over 90 minutes, and a healthcare professional will monitor you while you receive the treatment in case you experience any side effects (see section 2 "Warnings and precautions"). If you tolerate the first dose well, subsequent doses can be administered over 30 minutes. The number of infusions you receive will depend on your response to treatment. Your doctor will inform you about this.

To avoid medication errors, it is important that you check the labeling of the vial to ensure that the medicine being prepared and administered is Ontruzant (trastuzumab) and not another product containing trastuzumab (e.g., trastuzumab emtansine).

Ontruzant is administered every 3 weeks for early breast cancer, metastatic breast cancer, and metastatic gastric cancer. Ontruzant can also be administered once a week for metastatic breast cancer or trastuzumab deruxtecan).

If you stop treatment with Ontruzant

Do not stop using this medicine without talking to your doctor first. All doses should be administered at the right time every week or every three weeks (depending on your dosing schedule). This makes the medicine work as well as possible.

It may take up to 7 months for Ontruzant to be 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 further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Ontruzant can cause side effects, although not everybody gets them. Some of these side effects can be serious and may lead to hospitalization.

During administration of an Ontruzant infusion, 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 are: nausea, vomiting, pain, increased muscle tension, and agitation, headache, dizziness, difficulty breathing, high or low blood pressure, changes in heart rhythm (palpitations, arrhythmias, or irregular heartbeat), swelling of the face and lips, rash, and feeling of tiredness. Some of these symptoms can be severe, and some patients have died (see section 2 "Warnings and precautions").

These effects usually occur with 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 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 administered more slowly or the infusion will be stopped, and you may be given treatment to counteract the side effects. The infusion can be restarted once the symptoms have improved.

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

Severe side effects

Other side effects may occur at any time during treatment with Ontruzant, 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 severe. These include weakening of the heart muscle that may lead to heart failure, inflammation of the layer surrounding the heart, and changes in heart rhythm. This can cause symptoms such as shortness of breath (even if it is shortness of breath at night), cough, fluid retention (swelling) of the legs or arms, palpitations (arrhythmias or irregular heartbeat) (see section 2, "Heart checks").

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

• Tumor lysis syndrome (a set of metabolic complications that occur after cancer treatment and are characterized 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 (heart palpitations or a faster or slower heartbeat), seizures, vomiting, or diarrhea, and tingling in the mouth, hands, or feet.

If you experience any of the above symptoms after finishing treatment with Ontruzant, you should see your doctor and tell them that you have received treatment with Ontruzant.

The following side effects may occur at any time during treatment with Ontruzant, and not just related to the infusion.

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

• Infections
• Diarrhea
• Constipation
• Indigestion (heartburn)
• Fatigue
• Rash
• Chest pain
• Abdominal pain
• Joint pain
• Low levels of red and white blood cells (which help fight infections), sometimes with fever
• Muscle pain
• Conjunctivitis
• Excessive tearing
• Nosebleeds
• Runny nose
• Hair loss
• Tremors
• Hot flashes
• Dizziness
• Nail disorders
• Weight loss
• Loss of appetite
• Insomnia (inability to sleep)
• Altered taste
• Low levels of platelets
• Bruising
• Numbness or tingling in the fingers of the hands and feet, which may occasionally extend to the rest of the limb
• Redness, swelling, or sores in the mouth and/or throat
• Pain, swelling, redness, or tingling of the hands and/or feet
• Shortness of breath
• Headache
• Cough
• Vomiting
• Nausea

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

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

• Hearing loss
• Rash with bumps
• Wheezing (whistling)
• Inflammation/scarring of the lungs

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

• Jaundice (yellowing of the skin or eyes)
• Anaphylactic reactions

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

• Abnormal or altered blood clotting
• High levels of potassium
• Inflammation/bleeding in the back of the eyes
• Shock
• Abnormal heart rhythm
• 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 while lying down
• Liver damage
• Swelling of the face, lips, and throat
• Kidney failure

During pregnancy:

• Abnormally low levels of the fluid surrounding the fetus in the womb
• Inability 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 experience may be due to your cancer. If you are given Ontruzant with chemotherapy, some of the side effects may also be due to the chemotherapy.

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 it is possible side effects not listed in this leaflet. You can also report side effects directly through 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 Ontruzant

Ontruzant 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.
• The unopened vials should be stored in a refrigerator (between 2°C and 8°C).
• Do not freeze the reconstituted solution.
• The 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 and should, in general, not exceed 24 hours between 2°C and 8°C.
• Do not use this medicine if you notice particles or discoloration 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 Contents and Additional Information

Ontruzant Composition

• The active substance is trastuzumab. Each vial contains:

• 150 mg of trastuzumab to be dissolved in 7.2 ml of water for injectable preparations, or
• 420 mg of trastuzumab to be dissolved in 20 ml of 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.

Product Appearance and Container Contents

Ontruzant is a powder for concentrate for solution for intravenous infusion, supplied in a glass vial with a rubber stopper containing 150 mg or 420 mg of trastuzumab. The powder is a white to pale yellow pellet. Each box contains 1 vial of powder.

Marketing Authorization Holder

Samsung Bioepis NL B.V. Olof Palmestraat 10 2616 LR Delft Netherlands

Manufacturer

Samsung Bioepis NL B.V.

Olof Palmestraat 10

2616 LR Delft

Netherlands

For further information on this medicinal product, please contact the local representative of the marketing authorization holder:

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/.

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:

Ontruzant is provided in sterile, preservative-free, pyrogen-free, single-use vials.

To avoid medication errors, it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Ontruzant (trastuzumab) and not another product containing trastuzumab (e.g., trastuzumab emtansine or trastuzumab deruxtecan).

Always store this medicinal product in the original closed container at a temperature between 2°C and 8°C in a refrigerator.

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

The aseptically reconstituted vial of Ontruzant 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, the physical and chemical stability of Ontruzant 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 Ontruzant should be used immediately. If not used immediately, the storage time before use and storage conditions are the responsibility of the user and, in general, should not exceed 24 hours at 2°C to 8°C, unless 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 maintenance of aseptic conditions.

Ontruzant 150 mg Powder for Concentrate for Solution for Infusion

Each vial of Ontruzant 150 mg is reconstituted with 7.2 ml of water for injectable preparations (not supplied). The use of other solvents for reconstitution should be avoided. This produces a 7.4 ml single-dose solution containing approximately 21 mg/ml of trastuzumab. A 4% overfill allows the extraction of the 150 mg dose stated on the label from each vial.

Ontruzant 420 mg Powder for Concentrate for Solution for Infusion

Each vial of Ontruzant 420 mg is reconstituted with 20 ml of water for injectable preparations (not supplied). The use of other solvents for reconstitution should be avoided. This produces a 21 ml single-dose solution containing approximately 21 mg/ml of trastuzumab. A 5% overfill allows the extraction of the 420 mg dose stated on the label from each vial.

Instructions for Aseptic Reconstitution

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

• Using a sterile syringe, slowly inject the corresponding volume (as described above) of water for injectable preparations into the vial containing the Ontruzant lyophilisate, directing the flow towards the lyophilisate.
• Gently swirl the vial to aid in reconstitution. DO NOT SHAKE.

The formation of a slight foam after reconstitution is normal. Allow the vial to stand undisturbed for approximately 5 minutes. Reconstituted Ontruzant 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 a loading dose of 4 mg of trastuzumab/kg body weight or a subsequent weekly dose of 2 mg of trastuzumab/kg body weight:

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

The appropriate amount of solution should be withdrawn from the vial using a sterile needle and syringe and added to a polyvinyl chloride, polyethylene, or polypropylene infusion bag containing 250 ml of 0.9% sodium chloride injection. Glucose solutions should not be used. The bag should be gently inverted to mix the solution and avoid foam formation. Parenteral solutions should be visually inspected for particles and discoloration before administration.