AVTOZMA 20 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Avtozma 20 mg/ml Concentrate for Solution for Infusion

tocilizumab

This medicine is subject to additional monitoring, which will allow for the quick identification of new safety information. You can help by reporting any side effects you may have. The last section of section 4 will tell you how to report side effects.

Read all of this leaflet carefully before you start taking 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 nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

In addition to this leaflet, you will be given a patient information card, which contains important safety information that you should know before you receive Avtozma and during treatment with Avtozma.

Contents of the pack:

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

1. What is Avtozma and what is it used for

Avtozma contains the active substance tocilizumab, which is a protein obtained from specific immune cells (monoclonal antibody), which blocks the action of a specific type of protein (cytokine) called interleukin-6. This protein is involved in inflammatory processes in the body, and by blocking it, inflammation can be reduced. Avtozma helps reduce symptoms such as pain and swelling in your joints and can also improve your ability to perform daily tasks. Avtozma has been shown to slow down the progression of damage to the cartilage and bones of the joints caused by the disease and improve your ability to perform daily activities.

• Avtozma is used to treat adultswith moderate to severe active rheumatoid arthritis (RA), which is an autoimmune disease, if previous treatments have not worked well. Avtozma is normally used in combination with methotrexate. However, Avtozma may be given alone if your doctor decides that methotrexate is not suitable.

• Avtozma can also be used to treat adults who have not been previously treated with methotrexate if they have severe, active, and progressive rheumatoid arthritis.

• Avtozma is used in the treatment of children with sJIA. Avtozma is used in children aged 2 years and older who have active systemic juvenile idiopathic arthritis (sJIA), an inflammatory disease that causes pain and swelling in one or more joints, as well as fever and rash. Avtozma is used to improve the symptoms of sJIA and can be given alone or in combination with methotrexate.

• Avtozma is used in the treatment of children with pJIA. Avtozma is used in children aged 2 years and older with active polyarticular juvenile idiopathic arthritis (pJIA), an inflammatory disease that causes pain and swelling in one or more joints. Avtozma is used to improve the symptoms of pJIA and can be given in combination with methotrexate or alone.

• Avtozma is used in the treatment of adults and childrenaged 2 years and older with cytokine release syndrome (CRS)that is severe or life-threatening, an adverse effect in patients treated with chimeric antigen receptor (CAR) T cell therapy, used to treat certain types of cancer.

• Avtozma is used in the treatment of adultswith coronavirus disease 2019 (COVID-19), who are receiving systemic corticosteroids and require oxygen supplementation or mechanical ventilation.

2. What you need to know before you use Avtozma

You will not be given Avtozma

• If you are allergic to tocilizumab or any of the other ingredients of this medicine (listed in section 6). (See special warnings at the end of this section under the subtitle “Avtozma contains polysorbate”).
• If you have a severe active infection.

If any of these apply to you, talk to the doctor or nurse who will give you the infusion.

Warnings and precautions

Talk to your doctor or nurse before you start receiving Avtozma.

• If you experience allergic reactionssuch as chest tightness, wheezing, dizziness, or severe dizziness, swelling of the lips, or skin rash during or after the infusion, tell your doctor immediately.

• If you have any type of infection, either short-term or long-term, or if you get infections often, tell your doctor immediatelyif you feel unwell. Avtozma may reduce your body's ability to respond to infections and may make an existing infection worse or increase the likelihood of getting a new infection.

• If you have had tuberculosis, tell your doctor. Your doctor will check for signs and symptoms of tuberculosis before starting treatment with Avtozma. Tell your doctor immediately if symptoms of tuberculosis (persistent cough, weight loss, general malaise, low-grade fever), or any other infection appear during or after treatment.

• If you have had intestinal ulcer or diverticulitis, tell your doctor. Symptoms would include abdominal pain and unexplained changes in bowel habits with fever.

• If you have liver disease, tell your doctor. Before using Avtozma, your doctor will perform a blood test to measure your liver function.

• If a patient has been vaccinated recently(adult or child) or is scheduled to be vaccinated, tell your doctor. All patients, especially children, should be up to date with their vaccination schedule before starting treatment with Avtozma, unless urgent treatment is required. Certain types of vaccines should not be given while receiving Avtozma.

• If you have cancer, tell your doctor. Your doctor will decide whether you can continue treatment with Avtozma.

• If you have cardiovascular risk factors, such as high blood pressure and high cholesterol levels, tell your doctor. These factors need to be controlled while receiving treatment with Avtozma.

• If you have moderate to severe kidney problems, your doctor will monitor you.

• If you have persistent headaches.

Your doctor will perform blood tests before you receive Avtozma and during your treatment to determine if you have a low white blood cell count, a low platelet count, or elevated liver enzymes.

Children and adolescents

Avtozma is not recommended for use in children under 2 years of age.

Tell your doctor if the child has a history of macrophage activation syndrome, (uncontrolled activation and proliferation of specific blood cells). Your doctor will decide whether the child can continue to receive Avtozma.

Other medicines and Avtozma

Tell your doctor if you are taking, have recently taken, or might take any other medicines (or if your child is taking them, if they are the patient). This includes medicines obtained without a prescription. Avtozma may affect how some medicines work, and a dose adjustment may be needed. Tell your doctorif you are using medicines that contain any of these active substances:

• methylprednisolone, dexamethasone, used to reduce inflammation
• simvastatin or atorvastatin, used to reduce cholesterol levels
• calcium channel blockers, such as amlodipine, used to treat high blood pressure
• theophylline, used to treat asthma
• warfarin or phenprocoumon, used as anticoagulants
• phenytoin, used to treat seizures
• cyclosporin, used in organ transplants as an immunosuppressant
• benzodiazepines, such as temazepam, used to calm anxiety

Because there is no clinical experience, the use of tocilizumab with other biologic medicines used to treat RA, sJIA, or pJIA is not recommended.

Pregnancy, breastfeeding, and fertility

Avtozma should not be used during pregnancy, unless clearly necessary. Talk to your doctor if you are pregnant, think you may be pregnant, or plan to become pregnant.

Women of childbearing ageshould use effective contraceptive methods during and up to 3 months after finishing treatment.

Stop breastfeeding if you start treatment with Avtozma, and consult your doctor. Before restarting breastfeeding, at least 3 months should have passed since your last treatment with Avtozma. It is not known whether Avtozma passes into breast milk.

Data available so far do not suggest that this treatment has any effect on fertility.

Driving and using machines

This medicine may cause dizziness, if you feel dizzy, do not drive or use machines.

Avtozma contains polysorbate

This medicine contains 0.5 mg of polysorbate 80 per ml. Polysorbates can cause allergic reactions. Tell your doctor if you have any known allergy.

3. How to use Avtozma

This medicine is subject to medical prescription and will be administered by a doctor or nurse.

Avtozma will be given by intravenous infusion, by a doctor or nurse.They will dilute the solution, prepare the intravenous infusion, and monitor you during and after treatment.

Adult patients with RA

The usual dose of Avtozma is 8 milligrams (mg) per kilogram (kg) of body weight. Depending on the response, the doctor may decide to reduce the dose to 4mg/kg and then increase it back to 8 mg/kg when appropriate.

Adults will be given Avtozma once every 4 weeks through a vein (intravenous infusion) for one hour.

Children with sJIA (aged 2 years and older)

The usual dose of Avtozma depends on body weight.

• If you weigh less than 30 kg, the dose is 12 mg per kilogram of body weight.
• If you weigh 30 kg or more, the dose is 8 mg per kilogram of body weight.

The dose is calculated based on body weight at each administration.

Children with sJIA will be given Avtozma once every 2 weeks through a vein (intravenous infusion) for one hour.

Children with pJIA (aged 2 years and older)

The usual dose of Avtozma is calculated based on body weight.

• If you weigh less than 30 kg: the dose is 10 mg per kilogram of body weight.
• If you weigh 30 kg or more: the dose is 8 mg per kilogram of body weight.

The dose is calculated based on body weight at each administration.

Children with pJIA will receive Avtozma once every 4 weeks by intravenous infusion for one hour.

Patients with CRS

The usual dose of Avtozma is 8 mg per kilogram of body weight if you weigh 30 kg or more.

The dose is 12 mg per kilogram of body weight if you weigh less than 30 kg.

Avtozma may be given alone or in combination with corticosteroids.

Patients with COVID-19

The usual dose of Avtozma is 8 mg per kilogram of body weight. A second dose may be necessary.

If you are given too much Avtozma

Since Avtozma is administered by a doctor or nurse, it is unlikely that you will be given too much. However, if you are concerned, talk to your doctor.

If you miss a dose of Avtozma

Since Avtozma is administered by a doctor or nurse, it is unlikely that you will miss a dose. However, if you are concerned, talk to your doctor or nurse.

If you stop treatment with Avtozma

You should not stop treatment with Avtozma without talking to your doctor first.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects can occur up to at least 3 months after your last dose of Avtozma.

Serious side effects: talk to your doctor immediately.

These are common: May affect up to 1 in 10 people

Allergic reactionsduring or after the infusion:

• difficulty breathing, chest tightness, or dizziness
• skin rash, itching, hives, swelling of the lips, tongue, or face

If you experience any of these symptoms, talk to your doctor immediately.

Signs of serious infections

• fever and chills
• mouth or skin blisters
• stomach pain

Signs and symptoms of liver damage

May affect up to 1 in 1,000 people

• fatigue
• abdominal pain
• jaundice (yellowing of the skin or eyes)

If you notice any of these symptoms, tell your doctor as soon as possible.

Very common side effects:

May affect more than 1 in 10 people

• upper respiratory tract infections, with typical symptoms such as cough, nasal congestion, runny nose, sore throat, and headache
• high levels of fat in the blood (cholesterol)

Common side effects:

May affect up to 1 in 10 people

• lung infection (pneumonia)
• shingles (herpes zoster)
• fever (oral herpes), blisters
• skin infections (cellulitis), sometimes with fever and chills
• rash and itching, hives
• allergic reactions (hypersensitivity)
• eye infection (conjunctivitis)
• headache, dizziness, high blood pressure
• mouth ulcers, stomach pain
• fluid retention (edema) in the lower legs, weight gain
• cough, shortness of breath
• low white blood cell count in blood tests (neutropenia, leucopenia)
• abnormal liver function tests (elevated transaminases)
• increased bilirubin measured by blood tests
• low levels of fibrinogen in the blood (protein involved in blood clotting)

Uncommon side effects:

May affect up to 1 in 100 people

• diverticulitis (fever, nausea, diarrhea, constipation, stomach pain)
• swollen and red areas in the mouth
• high levels of fat in the blood (triglycerides)
• stomach ulcers
• kidney stones
• hypothyroidism

Rare side effects:

May affect up to 1 in 1,000 people

• Stevens-Johnson syndrome (skin rash that can lead to severe skin peeling)
• fatal allergic reactions (anaphylaxis)
• liver inflammation (hepatitis), jaundice

Very rare side effects:

May affect up to 1 in 10,000 people

• low levels of white blood cells, red blood cells, and platelets
• liver failure

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.

Children with sJIA

Generally, side effects in patients with sJIA were of a similar type to those in adults with RA. Some side effects were observed more frequently: inflammation of the nose and throat, diarrhea, decrease in white blood cell count, and increase in liver enzymes.

Children with pJIA

Generally, side effects in patients with pJIA were of a similar type to those in adults with RA. Some side effects were observed more frequently: inflammation of the nose and throat, headache, feeling unwell (nausea), and decrease in white blood cell count.

5. Storage of Avtozma

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. The expiry date refers to the last day of the month shown.

Store in a refrigerator (between 2°C and 8°C). Do not freeze.

Keep the vials in the outer packaging to protect them from light.

If necessary, the diluted solution for infusion in sodium chloride 0.9% or 0.45% injection solution can be stored for up to 1 month in refrigerated conditions or up to 48 hours at room temperature up to 30°C.

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

Composition of Avtozma

• The active substance is tocilizumab.

Each 4 ml vial contains 80 mg of tocilizumab (20 mg/ml).

Each 10 ml vial contains 200 mg of tocilizumab (20 mg/ml).

Each 20 ml vial contains 400 mg of tocilizumab (20 mg/ml).

• The other ingredients are L-histidine, L-histidine hydrochloride monohydrate, L-threonine, L-methionine, polysorbate 80, and water for injectable preparations.

Appearance and packaging of the product

Avtozma is a concentrate for solution for infusion. The concentrate is a clear to slightly opalescent, colorless to pale yellow liquid.

Avtozma is supplied in vials containing 4 ml, 10 ml, and 20 ml of concentrate for solution for infusion. Pack size of 1 and 4 vials. Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Manufacturer

Nuvisan France SARL

2400, Route des Colles,

06410, Biot,

France

Midas Pharma GmbH

Rheinstr. 49,

55218 Ingelheim,

Germany

KYMOS S.L.

Ronda Can Fatjó, 7B.

08290 Cerdanyola del Vallès,

Barcelona,

Spain

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

Date of last revision of this leaflet

Other sources of information

Detailed information on this medicinal product is available on the European Medicines Agency website https://www.ema.europa.eu and on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es.

This information is intended only for healthcare professionals:

Instructions for dilution prior to administration

Parenteral drugs should be inspected visually for particulate matter or color change prior to administration. Only solutions that are clear to slightly opalescent, colorless to pale yellow, and free of visible particles should be diluted. Use a sterile needle and syringe to prepare Avtozma. For polyvinyl chloride (PVC) infusion bags, use infusion bags that do not contain di(2-ethylhexyl)phthalate (DEHP-free).

Adult patients with RA, COVID-19, and sJIA (with weight ≥30 kg)

Remove from a 100 ml infusion bag a volume of sterile and apyrogenic sodium chloride solution 9 mg/ml (0.9%) or 4.5 mg/ml (0.45%) equal to the volume of Avtozma concentrate needed for the patient's dose, under aseptic conditions. The required amount of Avtozma concentrate (0.4 ml/kg) should be withdrawn from the vial and placed in the 100 ml infusion bag. The final volume should be 100 ml. To mix the solution, gently invert the infusion bag to avoid foam formation.

Use in pediatric population

Patient with sJIA, pJIA, and sJIA with weight ≥ 30 kg

Remove from a 100 ml infusion bag a volume of sterile and apyrogenic sodium chloride solution 9 mg/ml (0.9%) or 4.5 mg/ml (0.45%) equal to the volume of Avtozma concentrate needed for the patient's dose, under aseptic conditions. The required amount of Avtozma concentrate (0.4 ml/kg) should be withdrawn from the vial and placed in the 100 ml infusion bag. The final volume should be 100 ml. To mix the solution, gently invert the infusion bag to avoid foam formation.

Patient with sJIA and weight < 30 kg

Remove from a 50 ml infusion bag a volume of sterile and apyrogenic sodium chloride solution 9 mg/ml (0.9%) or 4.5 mg/ml (0.45%) equal to the volume of Avtozma concentrate needed for the patient's dose, under aseptic conditions. The required amount of Avtozma concentrate (0.6 ml/kg) should be withdrawn from the vial and placed in the 50 ml infusion bag. The final volume should be 50 ml. To mix the solution, gently invert the infusion bag to avoid foam formation.

Patient with pJIA and weight < 30 kg

Remove from a 50 ml infusion bag a volume of sterile and apyrogenic sodium chloride solution 9 mg/ml (0.9%) or 4.5 mg/ml (0.45%) equal to the volume of Avtozma concentrate needed for the patient's dose, under aseptic conditions. The required amount of Avtozma concentrate (0.5 ml/kg) should be withdrawn from the vial and placed in the 50 ml infusion bag. The final volume should be 50 ml. To mix the solution, gently invert the infusion bag to avoid foam formation.

Avtozma is for single use.

Any unused product or waste material should be disposed of in accordance with local requirements.