Avtozma

Package leaflet: Information for the user

Avtozma 20 mg/mL concentrate for solution for infusion

tocilizumab
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 this leaflet carefully before you are given this medicine, as 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 nurse.
• This medicine has been prescribed for you only.
• If you experience any side effect, including those not listed in this leaflet, inform your doctor or nurse. See section 4.

In addition to this package leaflet, you will be given a Patient Alert Card, which contains important safety information that you must know before being administered Avtozma and during treatment with Avtozma.
Contents of this leaflet:

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

1. What Avtozma is and what it is used for

Avtozma contains the active substance tocilizumab, a protein produced by specific immune cells (monoclonal antibody) that blocks the action of a specific protein (cytokine) called interleukin-6. This protein is involved in inflammatory processes in the body, and blocking it may reduce inflammation in your body. Avtozma helps reduce symptoms such as joint pain and swelling, and may also improve your ability to perform daily activities. Avtozma has been shown to slow down joint cartilage and bone damage caused by the disease and to improve your ability to carry out normal daily activities.

• Avtozma is used to treat adults with moderate to severe active rheumatoid arthritis (RA), an autoimmune disease, when previous treatments have not worked well enough. Avtozma is usually used in combination with methotrexate. Avtozma may also be used alone if your doctor considers methotrexate to be inappropriate.
• Avtozma may also be used to treat adult patients who have not previously been treated with methotrexate, if they have severe, active and progressive rheumatoid arthritis.
• Avtozma is used to treat children with sJIA. Avtozma is used in children aged 2 years and older who have active systemic juvenile idiopathic arthritis (sJIA), an inflammatory disease causing pain and swelling of one or more joints, accompanied by fever and rash. Avtozma is used to improve sJIA symptoms and may be given in combination with methotrexate or alone.
• Avtozma is used in children with pJIA. Avtozma is used in children aged 2 years and older with active polyarticular juvenile idiopathic arthritis (pJIA), an inflammatory disease causing pain and swelling of one or more joints. Avtozma is used to improve pJIA symptoms and may be administered in combination with methotrexate or alone.
• Avtozma is used to treat adults and children aged 2 years and older with severe or potentially life-threatening cytokine release syndrome (CRS), an adverse effect occurring in patients receiving CAR-T cell (chimeric antigen receptor T-cell) therapies used to treat certain malignant cancers.
• Avtozma is used to treat adults with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation.

2. What you should know before being given Avtozma

You must not be given Avtozma

• if you are allergic to tocilizumab or to any of the excipients of this medicine (listed in section 6) (see the special warnings at the end of this section under the subtitle “Avtozma contains polysorbate”)
• if you have an active severe infection. If either of these conditions applies to you, inform your doctor or nursing staff who are administering the infusion.

Warnings and precautions
Inform your doctor or nurse before you are given Avtozma.

• If you experience allergic reactions, such as chest tightness, wheezing, severe dizziness, a feeling of faintness, swelling of the lips or skin rash during or immediately after the infusion, inform your doctor immediately.
• If you have any infection, short- or long-term, or if you frequently get infections. Inform your doctor immediately if you feel unwell. Avtozma may reduce your body’s ability to respond to infections and could worsen an existing infection or increase the risk of developing a new infection.
• If you have had tuberculosis, inform your doctor. Your doctor will check for signs and symptoms of tuberculosis before starting treatment with Avtozma. If symptoms of tuberculosis (persistent cough, weight loss, fatigue, low-grade fever) or any other infection appear during or after treatment, inform your doctor immediately.
• If you have a history of intestinal ulcers or diverticulitis, inform your doctor. Symptoms may include abdominal pain and unexplained changes in bowel habits associated with fever.
• If you have liver disease, inform your doctor. Before using Avtozma, your doctor may want to perform a blood test to assess your liver function.
• If a patient has recently been vaccinated (whether adult or child), or plans to receive a vaccination, inform your doctor. All patients, especially children, should be up to date with all vaccinations before starting treatment with Avtozma, unless urgent initiation is required. Some types of vaccines should not be used during treatment with Avtozma.
• If you have a tumour, inform your doctor. Your doctor will need to decide whether you can still receive Avtozma.
• If you have cardiovascular risk factors, such as high blood pressure or elevated cholesterol levels, inform your doctor. These factors should be monitored while you are taking Avtozma.
• If you have moderate to severe renal impairment, your doctor will monitor you closely.
• If you have persistent headaches.

Your doctor will perform blood tests before administering Avtozma and during treatment
to check whether you have low levels of white blood cells or platelets, or elevated
liver enzyme levels.

Children and adolescents
The use of Avtozma is not recommended in children under 2 years of age.
If a child has a history of macrophage activation syndrome (uncontrolled activation and proliferation
of specific blood cells), inform the doctor. The doctor will need to decide whether the patient
can still receive Avtozma.

Other medicines and Avtozma
Inform your doctor if you are taking any other medicines (or if your child is the patient, if they are taking any medicines) or if you have recently taken any, including medicines obtained without a prescription. Avtozma may affect how some medicines work, and their doses may need adjustment. Inform your doctor if you are taking medicines containing the following active substances:

• methylprednisolone, dexamethasone, used to reduce inflammation
• simvastatin or atorvastatin, used to reduce cholesterol levels
• calcium channel blockers (e.g. amlodipine), used to treat high blood pressure
• theophylline, used to treat asthma
• warfarin or phenprocoumon, anticoagulants used to thin the blood
• phenytoin, used to treat seizures
• cyclosporine, used to suppress the immune system during organ transplantation
• benzodiazepines (e.g. temazepam), used to treat anxiety

Due to lack of clinical experience, tocilizumab is not indicated for use with other biological drugs for the treatment of RA, sJIA or pJIA.

Pregnancy, breastfeeding and fertility

Avtozma must not be used during pregnancy unless strictly necessary.
Inform your doctor if you are pregnant, think you may be pregnant, or are planning a pregnancy.
Women of childbearing potential must use an effective contraceptive method during treatment and for 3 months after the last dose.
Stop breastfeeding if you are about to be given Avtozma and inform your doctor.
At least 3 months must pass from the last dose of Avtozma before resuming breastfeeding.
It is not known whether Avtozma passes into breast milk.
Available data to date do not indicate an effect of this treatment on fertility.

Driving and using machines
This medicine may cause dizziness. If you experience dizziness, do not drive or operate machinery.

Avtozma contains polysorbate
This medicine contains 0.5 mg of polysorbate 80 per mL. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How Avtozma is administered

This medicine is subject to medical prescription limited by the physician.
Avtozma will be administered intravenously drop by drop by a doctor or nurse. They will dilute
a solution, prepare the intravenous infusion, and monitor you during and after
administration.
Adult patients with AR
The usual dose of Avtozma is 8 mg per kg of body weight. Depending on your response, your doctor
may reduce the dose to 4 mg/kg and increase it back to 8 mg/kg when appropriate.
In adult patients, Avtozma will be administered every 4 weeks via a one-hour intravenous
infusion (intravenous drip injection).
Children with AIGs (aged 2 years and older)
The usual dose of Avtozma depends on body weight.

• If body weight is less than 30 kg: the dose is 12 mg per kilogram of body weight.
• If body weight is 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.

In children with AIGs, Avtozma will be administered every 2 weeks via a one-hour intravenous
infusion (intravenous drip injection).
Children with AIGp (aged 2 years and older)
The usual dose of Avtozma depends on body weight.

• If body weight is less than 30 kg: the dose is 10 mg per kilogram of body weight.
• If body weight is 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.

In children with AIGp, Avtozma will be administered every 4 weeks via a one-hour intravenous
infusion (intravenous drip injection).
Patients with CRS
In patients weighing 30 kg or more, the usual dose of Avtozma is 8 mg per kilogram of body weight.
In patients weighing less than 30 kg, the dose is 12 mg per kilogram of body weight.
Avtozma may be administered alone or in combination with corticosteroids.
Patients with COVID-19
The recommended dose of Avtozma is 8 mg per kilogram of body weight. A second dose may be necessary.
If you are given more Avtozma than you should have
Since Avtozma will be administered by a doctor or nurse, it is unlikely that you will receive too much. However, if you have any concerns, speak to your doctor.
If you miss a dose of Avtozma
Since Avtozma will be administered by a doctor or nurse, it is unlikely that you will miss a dose. However, if you have any concerns, speak to your doctor or nurse.
If you stop treatment with Avtozma
You must not stop treatment with Avtozma without first discussing it with your doctor.
If you have any doubts about how to use this medicine, speak to your doctor or nurse.

4. Possible side effects

Like all medicines, Avtozma can cause side effects, although not everyone gets them. Side effects may occur up to 3 months after the last dose of Avtozma.

Possible serious common side effects: report immediately to your doctor.
These are common: they may affect up to 1 in 10 users

Allergic reactions during or after infusion:

• difficulty breathing, chest tightness, or dizziness
• skin rash, itching, hives, swelling of the lips, tongue, or face
  If you notice any of these symptoms, inform your doctor immediately.

Signs of serious infections

• fever and chills
• blisters in the mouth or on the skin
• stomach pain

Signs and symptoms of liver toxicity
These may affect up to 1 in 1,000 users

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

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

Very common side effects
These may affect more than 1 in 10 users

• upper respiratory tract infections with typical symptoms such as cough, nasal congestion, runny nose, sore throat, and headache
• elevated blood lipid levels (cholesterol)

Common side effects
These may affect up to 1 in 10 users

• lung infection (pneumonia)
• shingles (herpes zoster)
• cold sores (oral herpes simplex), blistering
• skin infections (cellulitis), sometimes associated with fever and chills
• skin 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 (neutropenia, leucopenia) detected by blood tests
• abnormalities in liver function tests (increased transaminases)
• increased bilirubin levels as shown in blood tests
• low levels of fibrinogen in the blood (a protein involved in blood clotting)

Uncommon side effects
These may affect up to 1 in 100 users

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

Rare side effects
These may affect up to 1 in 1,000 users

• Stevens-Johnson syndrome (skin rash, which may lead to severe blistering and skin peeling)
• fatal allergic reactions (anaphylaxis [fatal])
• liver inflammation (hepatitis), jaundice

Very rare side effects
These may affect up to 1 in 10,000 users

• low counts of white blood cells, red blood cells, and platelets in blood tests
• liver failure

Reporting of side effects
If you get any side effect, including those 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.
By reporting side effects, you can help provide more information on the safety of this medicine.

Children with AIGs
In general, in patients with AIGs, side effects similar to those in adult patients with RA have been observed. Some side effects occurred more frequently: inflammation of the nose and throat, diarrhea, low white blood cell count, and increased liver transaminases.

Children with AIGp
In general, side effects in AIGp patients were similar to those observed in adult RA patients. Some side effects occurred more frequently: inflammation of the nose and throat, headache, feeling unwell (nausea), and low white blood cell count.

5. How to store Avtozma

Keep Avtozma out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C). Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
If necessary, the solution for infusion diluted with 0.9% sodium chloride injection solution or with 0.45% sodium chloride injection solution may be stored in a refrigerator for up to 1 month or at room temperature not exceeding 30 °C for up to 48 hours.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Avtozma contains

• 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 excipients are L-histidine, L-threonine, L-methionine, polysorbate 80, and water for injections.

Description of the appearance of Avtozma and contents of the pack
Avtozma is a concentrate for solution for infusion. The concentrate is a liquid, from clear to slightly opalescent, from colourless to pale yellow.
Avtozma is supplied in vials containing 4 mL, 10 mL, and 20 mL of concentrate for solution for infusion. Packs of 1 and 4 vials are available. Not all pack sizes may be marketed.

Marketing Authorisation Holder
Celltrion Healthcare Hungary Kft.
1062 Budapest
Váci út 1-3. WestEnd Office Building B tower
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 Authorisation Holder:

België/Belgique/Belgien Lietuva
Celltrion Healthcare Belgium BVBA Celltrion Healthcare Hungary Kft.
Tél/Tel: +32 2 643 71 81 Tel.: +36 1 231 0493
[email protected]

България Luxembourg/Luxemburg
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Belgium BVBA
Teл.: +36 1 231 0493 Tél/Tel: +32 2 643 71 81
[email protected]

Česká republika Magyarország
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Tel: +36 1 231 0493 Tel:. +36 1 231 0493

Danmark Malta
Celltrion Healthcare Hungary Kft. Mint Health Ltd.
Tlf: +36 1 231 0493 Tel: +356 2093 9800

Deutschland Nederland
Celltrion Healthcare Deutschland GmbH Celltrion Healthcare Netherlands B.V.
Tel: +49(0)30 346494150 Tel: +31 20 888 7300
[email protected] [email protected]

Eesti Norge
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Tel: +36 1 231 0493 Tlf: +36 1 231 0493

España Österreich
CELLTRION FARMACEUTICA (ESPAÑA) Astro-Pharma GmbH
S.L. Tel: +43 1 97 99 860
Tel: +34 919 94 23 90

Ελλάδα Polska
ΒΙΑΝΕΞ Α.Ε. Celltrion Healthcare Hungary Kft.
Τηλ: +30 210 8009111 Tel.: +36 1 231 0493

France Portugal
Celltrion Healthcare France SAS CELLTRION PORTUGAL, UNIPESSOAL
Tél.: +33 (0)1 71 25 27 00 LDA.
Tel: +351 21 936 8542

Hrvatska România
Oktal Pharma d.o.o. Celltrion Healthcare Hungary Kft.
Tel: +385 1 6595 777 Tel: +36 1 231 0493

Ireland Slovenija
Celltrion Healthcare Ireland Limited OPH Oktal Pharma d.o.o.
Tel: +353 1 223 4026 Tel.: +386 1 519 29 22

Ísland Slovenská republika
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Sími: +36 1 231 0493 Tel: +36 1 231 0493

Italia Suomi/Finland
Celltrion Healthcare Italy S.r.l. Celltrion Healthcare Finland Oy.
Tel: +39 02 47927040 Puh/Tel: +358 29 170 7755

Κύπρος Sverige
C.A. Papaellinas Ltd Celltrion Sweden AB
Τηλ: +357 22741741 [email protected]

Latvija
Celltrion Healthcare Hungary Kft.
Tālr.: +36 1 231 0493

Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

Instructions for dilution prior to administration
Parenteral medications must be inspected visually before administration to ensure there are no particulate matters or discoloration. Only solutions that appear 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, DEHP-free (di-2-ethylhexyl phthalate-free) infusion bags must be used.

Adult patients with AR, COVID-19 and CRS (≥ 30 kg)
Under aseptic conditions, withdraw a volume of sterile, non-pyrogenic sodium chloride solution 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) from a 100 mL infusion bag equal to the volume of concentrated Avtozma required for the patient's dose. The required amount of concentrated Avtozma (0.4 mL/kg) should be withdrawn from the vial and added to the 100 mL infusion bag. The final volume must be 100 mL. To mix the solution, gently invert the infusion bag to avoid foaming.

Use in the pediatric population
Patients with AIGs, AIGp and CRS weighing ≥ 30 kg
Under aseptic conditions, withdraw a volume of sterile, non-pyrogenic sodium chloride solution 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) from a 100 mL infusion bag equal to the volume of concentrated Avtozma required for the patient's dose. The required amount of concentrated Avtozma ( 0.4 mL/kg ) should be withdrawn from the vial and added to the 100 mL infusion bag. The final volume must be 100 mL. To mix the solution, gently invert the infusion bag to avoid foaming.

Patients with AIGs and CRS weighing < 30 kg
Under aseptic conditions, withdraw a volume of sterile, non-pyrogenic sodium chloride solution 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) from a 50 mL infusion bag equal to the volume of concentrated Avtozma required for the patient's dose. The required amount of concentrated Avtozma ( 0.6 mL/kg ) should be withdrawn from the vial and added to the 50 mL infusion bag. The final volume must be 50 mL. To mix the solution, gently invert the infusion bag to avoid foaming.

Patients with AIGp weighing < 30 kg
Under aseptic conditions, withdraw a volume of sterile, non-pyrogenic sodium chloride solution 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) from a 50 mL infusion bag equal to the volume of concentrated Avtozma required for the patient's dose. The required amount of concentrated Avtozma (0.5 mL/kg) should be withdrawn from the vial and added to the 50 mL infusion bag. The final volume must be 50 mL. To mix the solution, gently invert the infusion bag to avoid foaming.

Avtozma is for single use only.
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.

Package leaflet: Information for the user

Avtozma 162 mg solution for injection in pre-filled syringe

tocilizumab
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 this leaflet carefully before taking this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

In addition to this patient information leaflet, you will be given a Patient Alert Card containing important safety information that you must know before starting and during treatment with Avtozma.
Contents of this leaflet:

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

1. What Avtozma is and what it is used for

Avtozma contains the active substance tocilizumab, a protein produced by specific immune cells (monoclonal antibody) that blocks the action of a specific protein (cytokine) called interleukin-6. This protein is involved in inflammatory processes in the body, and blocking it may reduce inflammation in your body. Avtozma is used to treat:

• Adults with moderate to severe active rheumatoid arthritis (RA), an autoimmune disease, when previous treatments have not been sufficiently effective.
• Adults with severe, active and progressive rheumatoid arthritis (RA) who have not been previously treated with methotrexate.

Avtozma helps reduce the symptoms of RA, such as joint pain and swelling, and may also improve your ability to perform daily activities. Avtozma has been shown to slow down joint damage to cartilage and bone caused by the disease and to improve your ability to carry out normal daily activities.
Avtozma is usually used in combination with another medicine for RA called methotrexate. However, Avtozma may be used alone if your doctor decides that treatment with methotrexate is inappropriate.

• Adults with a blood vessel disease called giant cell arteritis (GCA), caused by inflammation of the body's larger arteries, especially those supplying blood to the head and neck. Symptoms include headache, fatigue, and jaw/mouth pain. Complications may include stroke and blindness.

Avtozma can reduce pain and swelling of the arteries and veins in the head, neck, and arms.
GCA is often treated with medicines called steroids, which are generally effective but may cause side effects when used at high doses over long periods. In addition, reducing the steroid dose may lead to a flare-up of GCA. Adding Avtozma to treatment allows for shorter use of steroids while still maintaining control of GCA.

• Children and adolescents aged 1 year and older with active systemic juvenile idiopathic arthritis (sJIA), an inflammatory disease that causes pain and swelling in one or more joints, as well as fever and skin rash.

Avtozma is used to improve the symptoms of sJIA. It may be given in combination with methotrexate or alone.

• Children and adolescents 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. It may be given in combination with methotrexate or alone.

2. What you need to know before using Avtozma

Do not use Avtozma

• if you or a pediatric patient under your care are allergic to tocilizumab or to any of the excipients of this medicinal product (listed in section 6) (see special warnings at the end of this section under the subheading “Avtozma contains polysorbate”).
• if you or a pediatric patient under your care have an active severe infection.

If any of these conditions apply to you, inform your doctor. Do not use Avtozma.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Avtozma.

• If you experience allergic reactions, such as chest tightness, wheezing, severe dizziness or feeling faint, swelling of the lips or tongue, skin or facial itching, hives, or rash during or immediately after injection, inform your doctor immediately.
• If you experience any symptoms of an allergic reaction after receiving Avtozma, do not take the next dose until you have informed your doctor and the doctor has instructed you to continue.
• If you have an infection of any kind, short- or long-term, or if you have frequent infections. Inform your doctor immediately if you feel unwell. Avtozma may reduce the body’s ability to respond to infections and could worsen an existing infection or increase the risk of developing a new infection.
• If you have had tuberculosis, inform your doctor. Your doctor will check for signs and symptoms of tuberculosis before starting treatment with Avtozma. If symptoms of tuberculosis (persistent cough, weight loss, fatigue, low-grade fever) or any other infection occur during or after treatment, inform your doctor immediately.
• If you have had intestinal ulcers or diverticulitis, inform your doctor. Symptoms may include abdominal pain and unexplained changes in bowel habits associated with fever.
• If you have liver disease, inform your doctor. Before using Avtozma, your doctor may want to perform a blood test to assess liver function.
• If a patient has recently been vaccinated or is scheduled to be vaccinated, inform your doctor. All patients should be up to date with all vaccinations before starting treatment with Avtozma. Some types of vaccines should not be administered during treatment with Avtozma.
• If you have a tumor, inform your doctor. Your doctor will need to decide whether you can still receive Avtozma.
• If you have cardiovascular risk factors such as high blood pressure or elevated cholesterol levels, inform your doctor. These factors should be monitored while you are taking Avtozma.
• If you have moderate to severe renal impairment, your doctor will monitor you.
• If you have persistent headaches.

Your doctor will perform a blood test before administering Avtozma to determine whether you have low white blood cell or platelet counts, or elevated liver enzymes.
Children and adolescents
The use of Avtozma in the subcutaneous injectable solution is not recommended in children under 1 year of age. Avtozma must not be administered to children with sJIA weighing less than 10 kg.
If a child has a history of macrophage activation syndrome (uncontrolled activation and proliferation of specific blood cells), inform your doctor. The doctor will need to decide whether the patient can still be treated with Avtozma.
Other medicines and Avtozma
Inform your doctor if you are taking any other medicines or have recently taken any.
Avtozma may affect how some medicines work, and the dose of these medicines may need to be adjusted. Inform your doctor if you are taking medicines containing any of the following active substances:

• methylprednisolone, dexamethasone, used to reduce inflammation
• simvastatin or atorvastatin, used to lower cholesterol levels
• calcium channel blockers (e.g., amlodipine), used to treat high blood pressure
• theophylline, used to treat asthma
• warfarin or phenprocoumon, anticoagulants used to thin the blood
• phenytoin, used to treat seizures
• cyclosporine, used to suppress the immune system during organ transplantation
• benzodiazepines (e.g., temazepam), used to treat anxiety

Due to lack of clinical experience, tocilizumab is not indicated for use with other biological agents for the treatment of RA, sJIA, pJIA, or GCA.
Pregnancy, breastfeeding and fertility
Avtozma must not be used during pregnancy unless strictly necessary. Inform your doctor if you are pregnant, think you may be pregnant, or are planning a pregnancy.
Women of childbearing potential must use an effective contraceptive method during treatment and for 3 months after treatment ends.
Stop breastfeeding if you are about to be given Avtozma and inform your doctor. At least 3 months must pass after the last dose of Avtozma before breastfeeding is resumed. It is not known whether Avtozma passes into breast milk.
Driving and using machines
This medicine may cause dizziness. If you experience dizziness, do not drive or operate machinery.
Avtozma contains polysorbate
This medicine contains 0.2 mg of polysorbate 80 per pre-filled syringe. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How to use Avtozma

Always use this medicine exactly as instructed by your doctor, pharmacist, or nurse. If you are unsure, consult your doctor, pharmacist, or nurse.
Treatment will be prescribed and initiated by healthcare professionals experienced in the diagnosis and treatment of RA, SJIA, pJIA, or GCA.

Recommended dose
The dose for adults with RA and GCA is 162 mg (the content of 1 pre-filled syringe) administered once weekly.

Children and adolescents with SJIA (aged 1 year and older)
The usual dose of Avtozma depends on the patient's body weight.

• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled syringe) once every 2 weeks.
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled syringe) once weekly.

Children and adolescents with pJIA (aged 2 years and older)
The usual dose of Avtozma depends on the patient's body weight.

• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled syringe) once every 3 weeks.
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled syringe) once every 2 weeks.

Avtozma is administered by subcutaneous injection (under the skin). Initially, Avtozma may be administered by your doctor or nurse. However, your doctor may decide that you are able to self-inject Avtozma. In this case, you will be trained on how to self-administer Avtozma. Parents and caregivers of patients will be trained on how to administer Avtozma to patients who cannot self-inject, such as children.
Speak to your doctor if you have any questions about self-administering an injection or about administering it to a child in your care. Detailed “Instructions for Administration” can be found at the end of this leaflet.

If you use more Avtozma than you should
Since Avtozma is administered via a pre-filled syringe, it is unlikely that you will receive too much. However, if you have any concerns, speak to your doctor, pharmacist, or nurse.

If an adult with RA or GCA, or a child or adolescent with SJIA misses or forgets a dose
It is very important to use Avtozma exactly as prescribed by your doctor. Keep track of your next dose.

• If you missed a weekly dose and less than 7 days have passed since the missed dose, administer the dose on the next scheduled day.
• If you missed an alternate-week dose and less than 7 days have passed since the missed dose, inject the missed dose as soon as you remember, and administer the next dose at the regularly scheduled time.
• If more than 7 days have passed since the missed dose, or if you are unsure when to inject Avtozma, consult your doctor or pharmacist.

If a child or adolescent with pJIA misses or forgets a dose
It is very important to use Avtozma exactly as prescribed by your doctor. Keep track of the next dose.

• If a dose was missed and less than 7 days have passed since the missed dose, inject the dose as soon as you remember, and administer the next dose at the regularly scheduled time.
• If a dose was missed and more than 7 days have passed since the missed dose, or if you are unsure when to inject Avtozma, consult your doctor or pharmacist.

If you stop treatment with Avtozma
Do not stop treatment with Avtozma without first discussing it with your doctor.
If you have any doubts about using this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Avtozma can cause side effects, although not everybody gets them.
Side effects may occur up to 3 months or more after the last dose of Avtozma.

Serious common side effects: report immediately to your doctor.
These are common: they may affect up to 1 in 10 users

Allergic reactions during or after injection:

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

If you notice any of these symptoms, inform your doctor immediately.

Signs of serious infections:

• fever and chills
• blisters in the mouth or on the skin
• stomach pain

Signs and symptoms of liver toxicity
These may affect up to 1 in 1,000 users

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

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

Very common side effects:
May affect 1 in 10 patients or more

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

Common side effects:
May affect up to 1 in 10 patients

• lung infection (pneumonia)
• shingles (herpes zoster)
• cold sores (oral herpes simplex), blistering
• skin infections (cellulitis), sometimes associated 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 as shown in blood tests (neutropenia, leucopenia)
• abnormalities in liver function tests (increased transaminases)
• increased bilirubin levels as shown in blood tests
• low levels of fibrinogen in the blood (a protein involved in blood clotting)

Uncommon side effects:
May affect up to 1 in 100 patients

• diverticulitis (fever, nausea, diarrhoea, constipation, stomach pain)
• red, swollen areas in the mouth
• high levels of fats in the blood (triglycerides)
• gastric ulcer
• kidney stones
• hypothyroidism

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

• Stevens-Johnson syndrome (rash, which may lead to severe blistering and peeling of the skin)
• fatal allergic reactions (anaphylaxis [fatal])
• liver inflammation (hepatitis), jaundice

Very rare side effects:
May affect up to 1 in 10,000 patients

• low counts of white blood cells, red blood cells and platelets in blood tests
• liver failure

Side effects in children and adolescents with AIGs or AIGp
Side effects observed in children and adolescents with AIGs or AIGp are generally similar to those reported in adults. Some side effects occur more frequently in children and adolescents: inflammation of the nose and throat, headache, feeling unwell (nausea), and low white blood cell counts.

If you experience any of these side effects, inform your doctor, pharmacist or nurse. This includes any possible side effect not listed in this leaflet.

Reporting of side effects
If you get any side effect, including those 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. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Avtozma

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 pre-filled syringe (Exp.). The expiry date refers to the last day of the month.
Store in a refrigerator (2°C – 8°C). Do not freeze. After removal from the refrigerator, the pre-filled syringe may be stored for up to 3 weeks at a temperature not exceeding 30°C.
Keep pre-filled syringes in the outer packaging to protect them from light and moisture.
The medicine must not be used if the solution is cloudy or contains particles, if it is not transparent, or if it has a colour other than yellow, or if any part of the pre-filled syringe appears damaged.
The pre-filled syringe must not be shaken. After removing the cap, the injection must be administered within 5 minutes to prevent the medicine from drying and blocking the needle. If the pre-filled syringe is not used within 5 minutes after removing the cap, it must be disposed of in a puncture-resistant container and a new pre-filled syringe must be used.
If, after inserting the needle, the plunger cannot be pushed, the pre-filled syringe must be discarded into a puncture-resistant container and a new pre-filled syringe must be used.

6. Package Contents and Other Information

What Avtozma Contains

• The active substance is tocilizumab. Each 0.9 mL pre-filled syringe contains 162 mg of tocilizumab.
• The other excipients are L-histidine, L-threonine, L-methionine, polysorbate 80, and water for injections.

Description of the Appearance of Avtozma and Contents of the Pack
Avtozma is an injectable solution. The solution is from transparent to yellow.
Avtozma is supplied in a 0.9 mL pre-filled syringe containing 162 mg of tocilizumab injectable solution.
The pre-filled syringe of Avtozma for patient use is available in packs containing:

• 1 pre-filled syringe
• 4 pre-filled syringes
• 12 pre-filled syringes (3 packs of 4) (multiple packs)

Not all pack sizes may be marketed.
Marketing Authorization Holder
Celltrion Healthcare Hungary Kft.
1062 Budapest
Váci út 1-3. WestEnd Office Building B tower
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 on this medicinal product, please contact the local representative of the Marketing Authorization Holder:
België/Belgique/Belgien Lietuva
Celltrion Healthcare Belgium BVBA Celltrion Healthcare Hungary Kft.
Tél/Tel: +32 2 643 71 81 Tel.: +36 1 231 0493
[email protected]
България Luxembourg/Luxemburg
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Belgium BVBA
Teл.: +36 1 231 0493 Tél/Tel: +32 2 643 71 81
[email protected]
Česká republika Magyarország
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Tel: +36 1 231 0493 Tel:. +36 1 231 0493
Danmark Malta
Celltrion Healthcare Hungary Kft. Mint Health Ltd.
Tlf: +36 1 231 0493 Tel: +356 2093 9800
Deutschland Nederland
Celltrion Healthcare Deutschland GmbH Celltrion Healthcare Netherlands B.V.
Tel: +49 (0)30 346494150 Tel: + 31 20 888 7300
[email protected] [email protected]
Eesti Norge
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Tel: +36 1 231 0493 Tlf: +36 1 231 0493
España Österreich
CELLTRION FARMACEUTICA (ESPAÑA) Astro-Pharma GmbH
S.L. Tel: +43 1 97 99 860
Tel: +34 919 94 23 90
Ελλάδα Polska
ΒΙΑΝΕΞ Α.Ε. Celltrion Healthcare Hungary Kft.
Τηλ: +30 210 8009111 Tel.: +36 1 231 0493
France Portugal
Celltrion Healthcare France SAS CELLTRION PORTUGAL, UNIPESSOAL
Tél.: +33 (0)1 71 25 27 00 LDA.
Tel: +351 21 936 8542
Hrvatska România
Oktal Pharma d.o.o. Celltrion Healthcare Hungary Kft.
Tel: +385 1 6595 777 Tel: +36 1 231 0493
Ireland Slovenija
Celltrion Healthcare Ireland Limited OPH Oktal Pharma d.o.o.
Tel: +353 1 223 4026 Tel.: +386 1 519 29 22
Ísland Slovenská republika
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Sími: +36 1 231 0493 Tel: +36 1 231 0493
Italia Suomi/Finland
Celltrion Healthcare Italy S.r.l. Celltrion Healthcare Finland Oy.
Tel: +39 02 47927040 Puh/Tel: +358 29 170 7755
Κύπρος Sverige
C.A. Papaellinas Ltd Celltrion Sweden AB
Τηλ: +357 22741741 [email protected]
Latvija
Celltrion Healthcare Hungary Kft.
Tālr.: +36 1 231 0493
Other Sources of Information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu .

7. Instructions for Use

Read and follow the instructions for use included with your prefilled syringe of Avtozma before starting to use it each time you receive a refill. There may be new information. Before using Avtozma for the first time, a healthcare professional will show you how to use it correctly.

Important Information

• Do not remove the cap from the prefilled syringe until you are ready to inject Avtozma.
• Never attempt to disassemble the prefilled syringe.
• Never reuse the same syringe.
• Do not shake the prefilled syringe.
• Do not use the prefilled syringe if it has fallen or appears damaged.
• Patient information regarding hypersensitivity reactions (or anaphylaxis): if, during or after an injection, you develop at any time—while not in a clinical setting—symptoms such as, but not limited to, rash, itching, chills, swelling of the face, lips, tongue, or throat, chest pain, wheezing, difficulty breathing or swallowing, dizziness, or fainting, you must immediately go to the emergency room.

Storage of Avtozma

• Store the unused prefilled syringe in its original carton in the refrigerator at a temperature between 2 °C and 8 °C. Do not freeze.
• Once removed from the refrigerator, Avtozma may be stored for up to 3 weeks at a temperature not exceeding 30 °C. If not used within 3 weeks, Avtozma must be disposed of.
• Keep the prefilled syringe away from direct sunlight.
• Do not remove the prefilled syringe from its original carton during storage.
• Do not leave the prefilled syringe unattended.
• Keep the prefilled syringe out of the reach of children. It contains small parts.

Parts of the prefilled syringe (see Figure A).

Before use After use
Plunger
orange
Grip
white
Viewing
window
Medicine Needle
Needle
protection
Needle
cap
Figure A
Preparing the injection

1. Gather all necessary items for the injection.

Case
a. Prepare a clean, flat surface, such as a table or
containing the
countertop, in a well-lit area.
prefilled
b. Remove the case containing the prefilled syringe
syringe
from the refrigerator.
Cotton ball or
c. Make sure you have the following items ready (see
gauze pad and
Figure B):
alcohol wipe

• Case containing the prefilled Avtozma syringe
• Bandage
• Sharps disposal container
• Alcohol wipe

Sharps
disposal
container
Figure B

2. Check the carton

a. Examine the carton and make sure you have the correct medicine
(Avtozma) and the correct dosage.
b. Check the expiry date on the carton
to ensure it has not passed.

• Do not use the prefilled syringe if the expiry date has passed.
• Do not use the prefilled syringe if, when opening the carton for the first time, it appears to have been opened previously or is damaged; check that it is properly sealed.

Figure C

3. Inspect the prefilled syringe.

a. Open the carton and remove 1 single-dose prefilled syringe.
Return any remaining prefilled syringes of Avtozma in the carton to the refrigerator.
b. Check the expiration date printed on the Avtozma prefilled syringe ( see Figure D ).

• Do not use the prefilled syringe if the expiration date has passed. If the expiration date has passed, dispose of the prefilled syringe in a sharps container and take a new one.
  c. Examine the prefilled syringe to ensure it is not damaged and there are no signs of leakage.

• Do not use the prefilled syringe if it has been dropped, is damaged, or shows signs of liquid leakage.

Figure D

4. Wait 30 minutes.

a. Leave the prefilled syringe outside the case at
30 room temperature (between 20 °C and 25 °C) for
minutes 30 minutes to warm up (see Figure E).

• Do not warm the prefilled syringe using heat sources such as hot water or a microwave.
• Do not leave the prefilled syringe in direct sunlight.
• Do not remove the cap while the prefilled syringe is reaching room temperature.
• If the prefilled syringe does not reach room temperature, you may experience discomfort and have difficulty pushing the plunger.

Figure E

5. Inspect the medicine.

a. Hold the Avtozma with the cap pointing
downwards.
b. Look at the medicine and make sure that the liquid is
clear and colourless to pale yellow and does not
contain particles or flakes (see Figure F).

• Do not use the pre-filled syringe if the liquid is cloudy, discoloured, or contains particles or flakes. Dispose of the pre-filled syringe in a sharps container and use a new one.
• The presence of air bubbles is normal.

Figure F

6. Wash your hands.

a. Wash your hands thoroughly with water and soap, and dry them
(see Figure G).
Figure G

7. Choose an appropriate injection site (see

Figure H).
a. The areas where you can give the injection are:

• the front of the thighs;
• the abdomen, except for the area within 5 cm of the navel;
• the outer upper arms (only if the injection is administered by a caregiver or healthcare professional).
  • Do not self-administer the injection into the outer upper arms.
  • Each time an injection is given, a different site must be used, at least 2.5 cm away from the area used for the previous injection.
  • Do not inject into moles, scars, bruises, or areas where the skin is painful, red, or hardened.
  • Do not administer the injection through clothing. Figure H

8. Clean the injection site.

a. Disinfect the injection site using an alcohol swab
and let it air dry for about
10 seconds (see Figure I). This will reduce the
risk of infection.

• Make sure not to touch this area before administering the injection.
• Do not blow on or fan the disinfected area.

Figure I
Administration of the injection

9. Remove the cap.

a. Hold the pre-filled syringe in one hand by the barrel.
With the other hand, gently pull off the cap horizontally (see Figure J).
Note: If you cannot remove the cap, ask for help from the person assisting you or contact your healthcare provider.

• Do not hold the plunger while removing the cap.
• You may see a drop of liquid at the needle tip. This is normal.
• If the syringe is not used within 5 minutes after removing the needle cap, the pre-filled syringe must be discarded into a puncture-resistant container or sharps container, and a new pre-filled syringe must be used.
  b. Immediately dispose of the cap in a sharps container (see step 14 "Disposal of the pre-filled syringe" and Figure N).
• Do not reinsert the cap onto the pre-filled syringe.
• Do not touch the safety needle shield located at the tip of the pre-filled syringe to avoid accidental needlestick injury.

10. Insert the pre-filled syringe at the

injection site.
90°
45°
OK a. With one hand, gently pinch a fold of
skin at the injection site.
Note: This step is important to ensure
that the injection is administered under the skin (into the
subcutaneous tissue) and not deeper (into the muscle).
O

• Do not pull back the plunger.

b. Insert the needle fully into the skin fold at an angle
between 45° and 90°, using a quick, firm motion
(see Figure K).
90°
Note: Choosing the correct angle of insertion is
45° OK
important because it ensures that the medicine is
delivered under the skin (into the subcutaneous tissue);
otherwise, the injection may be painful and the medicine
may not be effective.
Figure K

• Do not touch the plunger while inserting the needle into the skin.

11. Administer the injection.

a. After inserting the needle, release the skin fold.
b. Slowly push the plunger all the way down until
the full dose of medicine has been delivered and
the syringe is empty (see Figure L).

• If you are unable to push the plunger down, you must dispose of the prefilled syringe and use a new prefilled syringe.
• Do not change the position of the prefilled syringe after you have started injecting the medicine.
• If the plunger is not fully depressed, the needle shield will not Figure L extend to cover the needle when it is withdrawn.
• If the needle is not covered, handle with caution and dispose of the syringe properly (see step 14 “Disposal of the prefilled syringe”).

12. Remove the prefilled syringe from the injection site.

Injection.
a. When the prefilled syringe is empty, remove the needle from the injection site and release the plunger until the needle is completely covered by the safety shield (see Figure M).

• Bleeding events may occur (see step 13 “Care of the injection site”).
• If the medicinal product comes into contact with the skin, wash the area with water.
• Do not reuse the prefilled syringe.

Figure M
After injection

13. Care of the injection site.

a. If you notice a small drop of blood, you may treat the injection site by gently pressing a cotton ball or gauze pad against the site without rubbing, and apply a plaster, if needed.

• Do not rub the injection site.

14. Disposal of the pre-filled syringe.

a. Place the pre-filled syringe into the sharps container immediately after use (see Figure N).
Note: If another person administers the injection to you, that person must be careful when removing and disposing of the pre-filled syringe to avoid accidental needlestick injury and transmission of infection.

• Do not reuse the pre-filled syringe.
• Do not recap the pre-filled syringe.
• Do not dispose of the sharps container in household waste.
• Do not recycle the sharps container.
• Keep Avtozma pre-filled syringe and the sharps container out of the reach of children.

Dispose of the full container according to instructions received from your healthcare provider or pharmacist. If you do not have a sharps container, you may use a closable, puncture-resistant household waste container. Any unused medicine and waste material arising from the medicine must be disposed of in accordance with local requirements.

15. Injection record.

a. Record the date, time, and specific body part where you administered the injection.

Package leaflet: Information for the user

Avtozma 162 mg solution for injection in pre-filled pen

tocilizumab
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 this leaflet carefully before using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

In addition to this package leaflet, you will be provided with a Patient Alert Card, which contains important safety information you must know before starting and during treatment with Avtozma.
Contents of this leaflet:

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

1. What Avtozma is and what it is used for

Avtozma contains the active substance tocilizumab, a protein produced by specific immune cells (monoclonal antibody) that blocks the action of a specific protein (cytokine) called interleukin-6. This protein is involved in inflammatory processes in the body, and blocking it may reduce inflammation in your body. Avtozma is used to treat:

• Adults with moderate to severe active rheumatoid arthritis (RA), an autoimmune disease, when previous treatments have not been sufficiently effective.
• Adults with severe, active and progressive rheumatoid arthritis (RA) who have not been previously treated with methotrexate.

Avtozma helps reduce the symptoms of RA, such as joint pain and swelling, and may also improve your ability to perform daily activities. Avtozma has been shown to slow down cartilage and bone damage in the joints caused by the disease and to improve your ability to carry out normal daily activities.
Avtozma is usually used in combination with another medicine for RA called methotrexate. However, Avtozma may be used alone if your doctor decides that treatment with methotrexate is inappropriate.

• Adults with a blood vessel disease called giant cell arteritis (GCA), caused by inflammation of the large arteries in the body, especially those supplying blood to the head and neck. Symptoms include headache, fatigue, and jaw/mouth pain. Complications may include stroke and blindness.

Avtozma can reduce pain and swelling of the arteries and veins in the head, neck, and arms.
GCA is often treated with medicines called steroids, which are generally effective but may cause unwanted side effects if used at high doses for prolonged periods. In addition, reducing the steroid dose may lead to a flare-up of GCA. Adding Avtozma to the treatment allows for shorter use of steroids while still keeping GCA under control.

• Children and adolescents aged 12 years and older with active systemic juvenile idiopathic arthritis (sJIA), an inflammatory disease causing pain and swelling in one or more joints, as well as fever and skin rash.

Avtozma is used to improve the symptoms of sJIA. It may be given in combination with methotrexate or alone.

• Children and adolescents aged 12 years and older with active polyarticular juvenile idiopathic arthritis (pJIA), an inflammatory disease causing pain and swelling in one or more joints.

Avtozma is used to improve the symptoms of pJIA. It may be given in combination with methotrexate or alone.

2. What you need to know before using Avtozma

Do not use Avtozma

• if you or a pediatric patient under your care are allergic to tocilizumab or to any of the other ingredients of this medicine (listed in section 6) (see the special warnings at the end of this section under the subtitle “Avtozma contains polisorbate”).
• if you or a pediatric patient under your care have an active severe infection.

If any of these conditions apply to you, inform your doctor. Do not use Avtozma.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Avtozma.

• If you experience allergic reactions, such as chest tightness, wheezing, severe dizziness or a feeling of fainting, swelling of the lips or tongue, skin or facial itching, hives or rash during or immediately after the injection, inform your doctor immediately.
• If you develop any symptoms of an allergic reaction after receiving Avtozma, do not take the next dose until you have informed your doctor and the doctor has instructed you to continue.
• If you have an infection, of any type and duration, or if you frequently get infections. Inform your doctor immediately if you feel unwell. Avtozma may reduce the body’s ability to respond to infections and could worsen an existing infection or increase the risk of developing a new infection.
• If you have had tuberculosis, inform your doctor. Your doctor will check for signs and symptoms of tuberculosis before starting treatment with Avtozma. If symptoms of tuberculosis (persistent cough, weight loss, fatigue, low-grade fever) or any other infection appear during or after treatment, inform your doctor immediately.
• If you have had intestinal ulcers or diverticulitis, inform your doctor. Symptoms may include abdominal pain and unexplained changes in bowel habits associated with fever.
• If you have liver disease, inform your doctor. Before using Avtozma, your doctor may want to perform a blood test to assess your liver function.
• If a patient has recently been vaccinated or plans to receive a vaccination, you must inform the doctor. All patients should be up to date with all vaccinations before starting treatment with Avtozma. Some types of vaccines should not be administered during treatment with Avtozma.
• If you have a tumor, inform your doctor. Your doctor will need to decide whether you can still receive Avtozma.
• If you have cardiovascular risk factors such as high blood pressure or elevated cholesterol levels, inform your doctor. These factors should be monitored while you are taking Avtozma.
• If you have moderate to severe renal impairment, your doctor will monitor you closely.
• If you have persistent headaches.

Your doctor will perform blood tests before administering Avtozma to determine whether you have
low white blood cell or platelet counts, or elevated liver enzymes.
Children and adolescents
The use of Avtozma in a pre-filled pen is not recommended in children under 12 years of age.
Avtozma must not be administered to children with sJIA weighing less than 10 kg.
If a child has a history of macrophage activation syndrome (uncontrolled activation and
proliferation of specific blood cells), inform the doctor. The doctor will need to decide whether the patient can still be treated with Avtozma.
Other medicines and Avtozma
Inform your doctor if you are taking or have recently taken any other medicines. Avtozma may affect how some medicines work, and the dose of these medicines may need to be adjusted. Inform your doctor if you are taking medicines containing the following active substances:

• methylprednisolone, dexamethasone, used to reduce inflammation
• simvastatin or atorvastatin, used to lower cholesterol levels
• calcium channel blockers (e.g., amlodipine), used to treat high blood pressure
• theophylline, used to treat asthma
• warfarin or phenprocoumon, anticoagulants used to thin the blood
• phenytoin, used to treat seizures
• cyclosporine, used to suppress the immune system during organ transplantation
• benzodiazepines (e.g., temazepam), used to treat anxiety.

Due to lack of clinical experience, tocilizumab is not indicated for use with other biological agents for the treatment of RA, sJIA, gJIA, or AOSD.
Pregnancy, breastfeeding, and fertility
Avtozma must not be used during pregnancy unless strictly necessary. Inform your doctor if you are pregnant, think you may be pregnant, or are planning a pregnancy.
Women of childbearing potential must use an effective contraceptive method during treatment and for at least 3 months after treatment ends.
Stop breastfeeding if you are about to be given Avtozma and inform your doctor. At least 3 months must pass after the last dose of Avtozma before breastfeeding can be resumed. It is not known whether Avtozma passes into breast milk.
Driving and using machines
This medicine may cause dizziness. If you feel dizzy, do not drive or operate machinery.
Avtozma contains polisorbate
This medicine contains 0.2 mg of polysorbate 80 per pre-filled syringe. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How to use Avtozma

Use this medicine exactly as instructed by your doctor, pharmacist, or nurse. If you have any doubts, please consult your doctor, pharmacist, or nurse.
Treatment must be prescribed and initiated by healthcare professionals experienced in the diagnosis and treatment of RA, JIA-s, JIA-p, or PsA.

Recommended dose
The dose for all adults with RA or PsA is 162 mg (the content of 1 pre-filled pen) administered once weekly.

Adolescents with JIA-s (aged 12 years and older)
The usual dose of Avtozma depends on the patient's body weight.

• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled pen) once every 2 weeks.
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled pen) once weekly.

The pre-filled pen must not be used to treat children under 12 years of age.

Adolescents with JIA-p (aged 12 years and older) The usual dose of Avtozma depends on the patient's body weight.

• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled pen) once every 3 weeks.
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled pen) once every 2 weeks.

The pre-filled pen must not be used to treat children under 12 years of age.
Avtozma is administered by subcutaneous injection (injected under the skin). Initially, Avtozma may be administered to you by your doctor or nurse. However, your doctor may decide that you are able to self-inject Avtozma. In this case, you will be trained on how to self-administer Avtozma. Parents and caregivers will also be trained on how to inject Avtozma in patients who are unable to self-inject the medicine.
Talk to your doctor if you have any questions about self-administering an injection or administering an injection to an adolescent patient under your care. At the end of this

Patient Information Leaflet, you will find detailed "Instructions for Administration".

If you use more Avtozma than you should
Since Avtozma will be administered to you using a pre-filled pen, it is unlikely that you will receive too much. However, if you have any concerns, contact your doctor, pharmacist, or nurse.

If an adult with RA or AS or an adolescent with PsA misses or forgets a dose
It is very important that you use Avtozma exactly as prescribed by your doctor. Keep track of your next dose.

• If you miss your weekly injection within 7 days, take the next scheduled dose.
• If you miss your alternate-week injection within 7 days, take the missed dose as soon as you remember, and take subsequent doses as scheduled.
• If you miss your weekly injection or your alternate-week injection for more than 7 days, or if you are unsure when to inject Avtozma, contact your doctor or pharmacist.

If an adolescent with pJIA misses or forgets a dose
It is very important to use Avtozma exactly as prescribed by your doctor. Keep track of your next dose.

• If a dose has been missed and less than 7 days have passed since the missed dose, inject a dose as soon as you remember, and administer the next dose regularly on the planned day and time.
• If a dose has been missed and more than 7 days have passed since the missed dose, or if you are unsure when to inject Avtozma, contact your doctor or pharmacist.

If you stop treatment with Avtozma
Do not stop treatment with Avtozma without first talking to your doctor.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Avtozma can cause side effects, although not everyone experiences them.
Side effects may occur up to 3 months or more after the last dose of Avtozma.

Possible serious side effects: report immediately to your doctor.
These are common: they may affect up to 1 in 10 patients

Allergic reactions during or after injection:

• difficulty breathing, chest tightness, or dizziness;
• skin rash, itching, hives, swelling of the lips, tongue, or face.
  If you notice any of these symptoms, inform your doctor immediately.

Signs of serious infections:

• fever and chills
• blisters in the mouth or on the skin
• stomach pain

Signs and symptoms of liver toxicity
These may affect up to 1 in 1000 users

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

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

Very common side effects:
May affect 1 in 10 patients or more

• upper respiratory tract infections with typical symptoms such as cough, nasal congestion, runny nose, sore throat, and headache
• elevated blood lipid levels (cholesterol)
• injection site reactions

Common side effects:
May affect up to 1 in 10 patients

• lung infection (pneumonia)
• shingles (herpes zoster)
• cold sores (oral herpes simplex), blistering
• skin infections (cellulitis), sometimes associated 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 as shown in blood tests (neutropenia, leucopenia)
• abnormalities in liver function tests (increased transaminases)
• increased bilirubin levels as shown in blood tests
• low levels of fibrinogen in the blood (a protein involved in blood clotting)

Uncommon side effects:
May affect up to 1 in 100 patients

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

Rare side effects:
These may affect up to 1 in 1000 users

• Stevens-Johnson syndrome (rash, which may lead to severe blistering and skin peeling)
• fatal allergic reactions (anaphylaxis [fatal])
• liver inflammation (hepatitis), jaundice

Very rare side effects:
May affect up to 1 in 10,000 patients

• low counts of white blood cells, red blood cells, and platelets in blood tests
• liver failure

Side effects in children and adolescents with AIGs or AIGp
Side effects observed in children and adolescents with AIGs or AIGp are generally similar to those reported in adults. Some side effects occur more frequently in children and adolescents: inflammation of the nose and throat, headache, feeling unwell (nausea), and lower white blood cell counts.

Reporting of side effects
If you experience any side effect, including those 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. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Avtozma

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 pre-filled pen (Exp). The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C-8 °C). Do not freeze. Once removed from the refrigerator, the pre-filled pen may be stored for up to 3 weeks at a temperature not exceeding 30°C.
Keep the pre-filled pens in their outer packaging to protect them from light and moisture.
The medicine must not be used if the solution is cloudy or contains particles, is not transparent, shows a colour other than yellow, or if any part of the pre-filled syringe appears damaged.
The pen must not be shaken. After removing the cap, the injection must be started within 3 minutes to prevent the medicine from drying and blocking the needle. If the pre-filled pen is not used within 3 minutes after removing the cap, it must be disposed of in a puncture-resistant container and a new pre-filled pen must be used.
If, after pressing the needle cover, the orange indicator does not move, the pre-filled pen must be discarded into a puncture-resistant container. Do not attempt to reuse the pre-filled pen. When reuse is attempted, the pre-filled pen becomes locked and the needle is covered inside the needle cover. Do not repeat the injection with another pre-filled pen. Contact your healthcare provider for assistance.

6. Package contents and other information

What Avtozma contains

• The active substance is tocilizumab. Each pre-filled pen contains 162 mg of tocilizumab in 0.9 mL.
• The other ingredients are L-histidine, L-threonine, L-methionine, polysorbate 80, and water for injections.

Description of the appearance of Avtozma and contents of the pack
Avtozma is an injectable solution. The solution is from clear to yellow.
Avtozma is supplied in a 0.9 mL pre-filled pen containing 162 mg of tocilizumab as an injectable solution.
The Avtozma pre-filled pen for patient use is available in packs containing:

• 1 pre-filled pen
• 4 pre-filled pens
• 12 pre-filled pens (3 packs of 4) (multiple packs)

Not all pack sizes may be marketed.
Marketing Authorization Holder
Celltrion Healthcare Hungary Kft.
1062 Budapest
Váci út 1-3. WestEnd Office Building B tower
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 medicine, please contact the local representative of the Marketing Authorization Holder:
België/Belgique/Belgien Lietuva
Celltrion Healthcare Belgium BVBA Celltrion Healthcare Hungary Kft.
Tél/Tel: +32 2 643 71 81 Tel.: +36 1 231 0493
[email protected]
България Luxembourg/Luxemburg
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Belgium BVBA
Teл.: +36 1 231 0493 Tél/Tel: +32 2 643 71 81
[email protected]
Česká republika Magyarország
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Tel: +36 1 231 0493 Tel:. +36 1 231 0493
Danmark Malta
Celltrion Healthcare Hungary Kft. Mint Health Ltd.
Tlf: +36 1 231 0493 Tel: +356 2093 9800
Deutschland Nederland
Celltrion Healthcare Deutschland GmbH Celltrion Healthcare Netherlands B.V.
Tel: +49 (0)30 346494150 Tel: + 31 20 888 7300
[email protected] [email protected]
Eesti Norge
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Tel: +36 1 231 0493 Tlf: +36 1 231 0493
España Österreich
CELLTRION FARMACEUTICA (ESPAÑA) Astro-Pharma GmbH
S.L. Tel: +43 1 97 99 860
Tel: +34 919 94 23 90
Ελλάδα Polska
ΒΙΑΝΕΞ Α.Ε. Celltrion Healthcare Hungary Kft.
Τηλ: +30 210 8009111 Tel.: +36 1 231 0493
France Portugal
Celltrion Healthcare France SAS CELLTRION PORTUGAL, UNIPESSOAL
Tél.: +33 (0)1 71 25 27 00 LDA.
Tel: +351 21 936 8542
Hrvatska România
Oktal Pharma d.o.o. Celltrion Healthcare Hungary Kft.
Tel: +385 1 6595 777 Tel: +36 1 231 0493
Ireland Slovenija
Celltrion Healthcare Ireland Limited OPH Oktal Pharma d.o.o.
Tel: +353 1 223 4026 Tel.: +386 1 519 29 22
Ísland Slovenská republika
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Sími: +36 1 231 0493 Tel: +36 1 231 0493
Italia Suomi/Finland
Celltrion Healthcare Italy S.r.l. Celltrion Healthcare Finland Oy.
Tel: +39 02 47927040 Puh/Tel: +358 29 170 7755
Κύπρος Sverige
C.A. Papaellinas Ltd Celltrion Sweden AB
Τηλ: +357 22741741 [email protected]
Latvija
Celltrion Healthcare Hungary Kft.
Tālr.: +36 1 231 0493
Other sources of information
More detailed information on this medicine is available on the website of the European Medicines Agency, https://www.ema.europa.eu/.

7. Instructions for Use

Read and follow the instructions for use provided with your pre-filled Avtozma pen each time you receive a new supply, before starting to use it. There may be new information. Before using Avtozma for the first time, a healthcare professional will show you how to use it correctly.

Important Information

• Do not remove the cap of the pre-filled pen until you are ready to inject Avtozma.
• Do not ever attempt to disassemble the pre-filled pen.
• Do not reuse the same pen.
• Do not shake the pre-filled pen.
• Do not use the pre-filled pen if it has been dropped or appears damaged.
• Patient information regarding hypersensitivity reactions (or anaphylaxis): if, during or after an injection, you develop any symptoms—such as, but not limited to, rash, itching, chills, swelling of the face, lips, tongue or throat, chest pain, wheezing, difficulty breathing or swallowing, dizziness or fainting—while not in a clinical setting, you must immediately go to the emergency room.

Storage of Avtozma

• Store the unused pre-filled pen in its original carton in the refrigerator at a temperature between 2 °C and 8 °C. Do not freeze.
• Once removed from the refrigerator, Avtozma may be stored for up to 3 weeks at a temperature not exceeding 30 °C. If not used within 3 weeks, Avtozma must be discarded.
• Keep the pre-filled pen away from direct sunlight.
• Do not remove the pre-filled pen from its original carton during storage.
• Do not leave the pre-filled pen unattended.
• Keep the pre-filled pen out of the reach of children. It contains small parts.

Parts of the Avtozma pre-filled pen (see Figure A).

After use
Before use
Expiry date
Body
Indicator
Orange window
“injection
complete”
Cap
Blue needle
Blue needle
cap
cap (needle
(locked and
inside)
needle inside)
Orange cap
Figure A
Preparing the Injection

1. Gather all necessary items for the injection.

a. Prepare a clean, flat surface, such as a table or countertop, in a well-lit area.
b. Remove the pre-filled pen pack from the refrigerator.
c. Make sure you have the following items ready (see Figure B):

• Pack containing the pre-filled pen of Avtozma

Not supplied in the pack:

• Cotton ball or gauze
• Adhesive bandage
• Sharps container
• Alcohol swab

Figure B

2. Inspect the carton

a. Examine the carton and make sure you have the correct medicine (Avtozma) and dosage.
b. Check the expiration date printed on the carton to ensure it has not passed.

• Do not use the pre-filled pen if the expiration date has passed.
• If you are opening the carton for the first time, ensure it is properly sealed.
• Do not use the pre-filled pen if you think the carton has been opened or damaged.

Figure C

3. Inspect the pre-filled pen.

a. Open the carton and remove 1 pre-filled single-dose pen.
Return any remaining Avtozma pre-filled pens in the carton to the refrigerator.
b. Check the expiration date printed on the Avtozma pre-filled pen ( see Figure D ).

• Do not use the pre-filled pen if the expiration date has passed. If the expiration date has passed, dispose of the pre-filled pen in a sharps container and take a new one.
  c. Examine the pre-filled pen to ensure it is not damaged and there are no signs of liquid leakage.
• Do not use the pre-filled pen if it has been dropped, damaged, or shows signs of leakage.
  Note: A small gap between the orange cap and the body of the injector is normal.

Figure D

4. Wait 45 minutes.

a. Leave the prefilled pen outside the case at
45 room temperature (between 20 °C and 25 °C) for
45 minutes to allow it to warm up (see Figure E).
minutes

• Do not warm the prefilled pen using heat sources such as hot water or microwave.
• Do not leave the prefilled pen in direct sunlight.
• Do not remove the cap while the prefilled pen is reaching room temperature.
• If the prefilled pen does not reach room temperature, you may experience discomfort.

Figure E

5. Inspect the medicine.

a. Hold Avtozma with the cap pointing
downwards.
b. Look at the medicine and make sure the liquid is
from clear to slightly opalescent and from colourless to
yellow, and that it does not contain particles or flakes (see
Figure F).

• Do not use the pre-filled pen if the liquid is cloudy, discoloured, or contains particles or flakes. Dispose of the pre-filled pen in a sharps container and use a new one.
• The presence of air bubbles is normal.

Figure F

6. Wash your hands.

a. Wash your hands thoroughly with water and soap and dry them
(see Figure G).
Figure G

7. Choose an appropriate injection site (see

Figure H).
a. Injection sites include:

• the front of the thighs;
• the abdomen, except for the area within 5 cm of the navel;
• the outer area of the upper arms (only if the injection is administered by a caregiver or healthcare professional).
  • Do not self-administer the injection into the outer area of the upper arms.
  • Each injection should be given at a different site, at least 2.5 cm away from the area used for the previous injection.
  • Do not administer the injection into moles, scars, bruises, or areas where the skin is tender, red, or hardened.

Figure H

8. Clean the injection site.

a. Disinfect the injection site using an alcohol swab and let it air dry (see Figure I). This will reduce the risk of infection.

• Make sure not to touch this area before administering the injection.
• Do not blow on or fan the disinfected area.

Figure I
Administration of the injection

9. Remove the cap.

a. Hold the pre-filled pen in one hand,
gripping the body of the injector with the
cap still in place.
With the other hand, gently pull off the cap
Needle
by pulling it horizontally (see Figure J).
Cover
Note: If you are unable to remove the cap, ask
for help from your caregiver or contact your
healthcare provider.
b. Immediately dispose of the cap in a
sharps container (see step 14 and
Figure O).

• Do not reinsert the cap onto the pre-filled pen.
• Do not touch the safety shield covering the needle at the tip of the pre-filled pen to avoid accidental needlestick injury.
• Once the cap has been removed, the pre-filled pen is ready for use. If it is not used within 3 minutes after cap removal, the pre-filled pen must be discarded into a sharps container and a new pre-filled pen must be used.

Figure J

10. Insert the pre-filled pen into the injection site.

a. With one hand, hold the pre-filled pen comfortably, ensuring you can see the viewing window (see Figure K).
b. Without pinching or pulling the skin, insert the pre-filled pen into the skin at a 90° angle (see Figure L).
Note: Choosing the correct angle is important, as it ensures the medicine is delivered under the skin (into the fatty tissue); otherwise, the injection may be painful and the medicine may not be effective.

• Do not inject the medicine into a muscle or a Figure K blood vessel.

90°
OR
90°
Figure L

11. Administer the injection.

a. Press the pre-filled pen firmly into the skin
to start the injection.
b. When the injection starts, you will hear the first "click" and
the orange indicator will begin to fill the window
1st
(see Figure M).
click
c. Keep the pre-filled pen firmly pressed against the skin
until you hear the second "click".
d. After hearing the second "click", continue to hold
the pre-filled pen firmly against the skin and count slowly to 5 to ensure the full dose is delivered (see Figure M).
e. Follow the orange indicator until it stops moving and reaches the end of the window to make sure the complete dose of medicine has been injected.
Note: If the orange indicator does not move, discard the pre-filled pen and use a new one.
2nd
click
Then count
slowly to 5
Figure M

12. Remove the pre-filled pen from the injection site.

injection.
a. When the orange indicator stops, lift the pre-filled pen away from the injection site at a 90° angle to remove the needle from the skin.

• The needle cover will automatically come off and lock into place, covering the needle (see Figure N). Note: If the viewing window has not turned completely orange or if medication is still being injected, this means the full dose has not been delivered. Carefully dispose of the pre-filled pen into a sharps container and contact your healthcare provider immediately.

Figure N • Do not touch the needle cover of the pre-filled pen.

• Do not attempt to reuse the pre-filled pen.
• Do not repeat the injection using another pre-filled pen.

After the injection

13. Care of the injection site.

a. If you notice a few drops of blood, you may treat the injection site by gently pressing, without rubbing, a cotton ball or gauze pad against the site and applying a plaster, if necessary.

• Do not rub the injection site.

14. Disposal of Avtozma.

a. Place the pre-filled pen into the sharps container immediately after use (see Figure O).
Note: if the injection is administered by someone else, that person must be cautious when removing the pre-filled pen and disposing of it, in order to avoid accidental needle-stick injury and transmission of infection.

• Do not reuse the pre-filled pen.
• Do not reinsert the cap onto the pre-filled pen.
• Do not dispose of the used sharps container in household waste.
• Do not recycle the used sharps container.
• Keep the Avtozma pre-filled pen and the sharps container out of the reach of children.
• Dispose of the full container according to the instructions provided by your healthcare professional or pharmacist. If a sharps container is not available, you may use a resealable, puncture-resistant container for household waste. Unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.

Figure O

15. Recording the injection.

a. Record the date, time, and specific body site where you administered the injection.