TYRUKO 300 MG CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Tyruko 300mg concentrate for solution for infusion

natalizumab

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

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

In addition to this leaflet, you will be given a patient alert card. This contains important safety information that you should be aware of before and during treatment with Tyruko.

• Keep this leaflet and the patient alert card, as you may need to read them again. Keep the leaflet and the patient alert card with you during treatment and for six months after the last dose of this medicine, as side effects can occur even after treatment has stopped.
• If you have any further questions, ask your doctor.
• If you experience any side effects, talk to your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the pack:

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

1. What Tyruko is and what it is used for

Tyruko is used to treat multiple sclerosis (MS). It contains the active substance natalizumab. It is what is called a monoclonal antibody.

MS causes inflammation in the brain that damages nerve cells. This inflammation occurs when white blood cells enter the brain and spinal cord. This medicine prevents white blood cells from entering the brain. This reduces nerve damage caused by MS.

Multiple sclerosis symptoms

The symptoms of MS can vary from person to person; you may experience some or none.

They may include: problems with walking, tingling in the face, arms, or legs; vision problems; fatigue; feeling unsteady or dizzy; bladder and bowel problems; difficulty thinking and concentrating; depression; acute or chronic pain; sexual problems; muscle stiffness and spasms. When symptoms worsen, it is called a relapse(also exacerbation or flare-up). When a relapse occurs, you may notice symptoms suddenly, within hours, or with a slow progression over several days. Symptoms usually improve gradually (this is called remission).

How Tyruko can help

In trials, this medicine reduced the increase in disability caused by MS by about half and reduced the number of MS relapses by about two-thirds. While you are being treated with this medicine, you may not notice any improvement, but it can continue to work to prevent MS from getting worse.

2. What you need to know before you are given Tyruko

Before starting treatment with this medicine, it is important that you and your doctor have discussed the benefits you can expect from this treatment and the risks associated with it.

You should not be given Tyruko

• If you are allergicto natalizumab or any of the other ingredients of this medicine (listed in section 6).

• If you have been diagnosed with progressive multifocal leukoencephalopathy (PML). PML is a rare brain disease.

• If your immune systemhas a serious problem. This can be due to a disease (such as HIV infection) or medicines you are taking or have taken in the past (see below).

• If you are taking medicines that affect the immune system, including certain medicines used to treat MS. These medicines cannot be used with Tyruko.

• If you have cancer(unless it is a type of skin cancer called basal cell carcinoma).

Warnings and precautions

Talk to your doctorif Tyruko is the right treatment for you. Do this before starting to use Tyruko and when you have been receiving it for more than two years.

Possible brain infection (PML)

Some people who receive this medicine (less than 1 in 100) have had a rare brain infection called PML (progressive multifocal leukoencephalopathy). PML can cause severe disability or death.

• Before starting treatment, your doctor will perform a blood test on all patientsto detect JC virus infection. The JC virus is a common virus that usually does not make you sick. However, PML is associated with an increase in JC virus in the brain. The reason for this increase in some patients treated with Tyruko is not clear. Before and during treatment, your doctor will perform a blood test to check if you have antibodies against the JC virus (anti-JCV antibodies), which are a sign that you have been infected with the JC virus.

• Your doctor will perform an MRI scan, which will be repeated during treatment to rule out PML.

• Symptoms of PMLcan be similar to those of an MS relapse (see section 4, Possible side effects). You can also develop PML up to 6 months after stopping treatment with Tyruko.

• Tell your doctor as soon as possibleif you notice that your MS is getting worse or if you notice any new symptoms while you are being treated with Tyruko or up to 6 months after.

• Tell your partner or caregiverswhat to look out for (see also section 4, Possible side effects). Some symptoms can be difficult to detect by yourself, such as mood or behavior changes, confusion, speech and communication difficulties. If you experience any of these, you may need to have more tests. Be aware of symptoms during the 6 months after stopping Tyruko.

• Keep the patient alert card that your doctor has given you. It includes this information. Show it to your partner or caregivers.

Three things can increase the risk of PMLwith Tyruko. If you have two or more of these risk factors, the risk increases even more:

• If you have anti-JCV antibodiesin your blood. They are a sign that the virus is in your body. You will have tests before and during treatment with Tyruko.

• If you are receiving long-term treatmentwith Tyruko, especially if it is for more than two years.

• If you have taken a medicine known as animmunosuppressant, which reduces the activity of your immune system.

The JC virus also causes another condition, called JCV granule cell neuronopathy (JCV-GCN), which has occurred in some patients receiving treatment with Tyruko. The symptoms of JCV-GCN are similar to the symptoms of PML.

In the case of patients with a lower risk of PML, your doctor may repeat tests periodically to check:

• If you still do not have anti-JCV antibodies in your blood.

• If you have received treatment for more than 2 years, if you still have a lower level of anti-JCV antibodies in your blood.

If someone develops PML

PML can be treated, and treatment with Tyruko will be stopped. However, some people may experience a reaction when Tyruko is removed from the body. This reaction (known as IRIS or immune reconstitution inflammatory syndrome) can make your condition worse, including worsening of brain function.

Be aware of other infections

Some infections other than PML can also be serious and can be caused by viruses, bacteria, and other causes.

Tell your doctor or nurse immediatelyif you think you have an infection (see also section 4, Possible side effects).

Changes in blood platelet count

Natalizumab can reduce the number of platelets in the blood, which are responsible for blood clotting. This can lead to a disorder called thrombocytopenia (see section 4) by which your blood may not clot quickly enough to stop bleeding. This can cause bruising, as well as more serious problems such as excessive bleeding. Tell your doctor immediately if you have unexplained bruising, red or purple spots on the skin (called petechiae), bleeding from cuts in the skin that do not stop or ooze, prolonged bleeding from the gums or nose, blood in the urine or stool, or bleeding in the white part of the eyes.

Children and adolescents

Do not give this medicine to children or adolescents under 18 years of age.

Other medicines and Tyruko

Tell your doctor if you are using, have recently used, or might use any other medicines.

• You should not be giventhis medicine if you are currently being treated with medicines that affect your immune system, including certain medicines for the treatment of MS.

• It is possiblethat you may not be able to use this medicine if you have ever taken a medicine that affects the immune system.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before using this medicine.

• Do not use this medicine if you are pregnant,unless you have discussed it with your doctor. If you are pregnant, think you may be pregnant, or are planning to have a baby, you must tell your doctor immediately.

• Do not breastfeed while using Tyruko.Your doctor will help you decide whether to stop breastfeeding or stop using the medicine.

Your doctor will consider the risk to the baby and the benefit to the mother.

Driving and using machines

Dizziness is a very common side effect. If you experience this symptom, do not drive or use machines.

Tyruko contains sodium

Each vial of this medicine contains 2.3 mmol (52 mg) of sodium. After dilution before use, the medicine contains 17.7 mmol (406 mg) of sodium per dose. You should be aware of this if you are on a low-sodium diet.

3. How Tyruko is given

Tyruko IV infusion should be given to you by a doctor who has experience in treating MS. Your doctor may switch you directly from the treatment you are receiving for your MS to Tyruko if no problems are seen with the previous treatment.

• Your doctor will request blood teststo detect anti-JCV antibodies and other possible problems.

• Your doctor will perform an MRI scan, which will be repeated during treatment.

• To switch from some MS medicines,your doctor may recommend that you wait for a certain time to make sure that most of the previous medicine has been removed from your body.

• The recommended dose for adults is 300 mg once every four weeks.

• Tyruko must be diluted before it is given to you. It is given through a drip into a vein (by intravenous infusion), usually in the arm. Administration takes about 1 hour.

• At the end of this leaflet, information is provided on how to prepare and administer the medicine intended for healthcare professionals.

If you stop treatment with Tyruko

It is important to continue taking Tyruko, especially during the first few months of treatment. It is important that you continue treatment while you and your doctor decide that it is helping you. Patients who received one or two doses of Tyruko and then took a break in treatment of three months or more had a higher chance of having an allergic reaction when treatment was restarted.

Checking for allergic reactions

Some patients have had an allergic reaction to this medicine. Your doctor may check for allergic reactions during the infusion and for 1 hour after. See also section 4, Possible side effects.

If you miss a dose of Tyruko

If you did not receive your usual dose of Tyruko, talk to your doctor so that it can be given to you as soon as possible. After that, you can continue to receive Tyruko every four weeks.

Will Tyruko always work?

In some patients who receive Tyruko, the body's natural defenses can prevent the medicine from working properly over time as the body produces antibodies against the medicine. Your doctor may decide if this medicine is not working properly for you based on your blood tests and stop treatment if necessary.

If you have any further questions on the use of Tyruko, ask your doctor. Follow exactly the instructions of administration of the medicine contained in this leaflet or given by your doctor. In case of doubt, ask your doctor.

4. Possible Adverse Effects

Like all medicines, this medicine may cause adverse effects, although not all people suffer from them.

Tell your doctor or nurse immediatelyif you notice any of the following symptoms.

Signs of Brain Infection

• Changes in personality and behavior such as confusion, delirium, or loss of consciousness
• Seizures (epileptic attacks)
• Headache
• Nausea/Vomiting
• Neck stiffness
• Extreme sensitivity to bright light
• Fever
• Skin rash (on any part of the body)

These symptoms may be due to a brain infection (encephalitis or PML) or the membrane that covers it (meningitis).

Signs of Other Serious Infections

• Unexplained fever
• Severe diarrhea
• Shortness of breath
• Prolonged dizziness
• Headache
• Weight loss
• Lack of energy
• Visual disturbance
• Pain or redness of the eye(s)

Signs of Allergic Reaction

• Hives (itchy rash)
• Swelling of the face, lips, or tongue
• Difficulty breathing
• Chest pain or discomfort
• Increased or decreased blood pressure (your doctor or nurse will alert you if they are monitoring your blood pressure)

It is more likely to occur during or shortly after infusion.

Signs of Possible Liver Problem

• Yellowing of the skin or whites of the eyes
• Unusual darkening of urine
• Abnormal liver function test

If you experience any of the adverse effects described above or if you think you have an infection, consult your doctor or nurse immediately. Show your patient alert cardand this leaflet to any doctor or nurse who treats you, not just your neurologist.

Other Adverse Effects

Very Common(may affect more than 1 in 10 people)

• Urinary tract infection
• Sore throat and nasal congestion or secretion
• Headache
• Dizziness
• Feeling unwell (nausea)
• Joint pain
• Fatigue
• Dizziness, feeling unwell (nausea), itching, and chills during or shortly after infusion

Common(may affect up to 1 in 10 people)

• Anemia (reduced number of red blood cells that can make your skin pale and make you feel short of breath or lacking energy)
• Allergy (hypersensitivity)
• Chills
• Hives (itchy rash)
• Vomiting
• Fever
• Difficulty breathing (dyspnea)
• Redness of the face or body (flushing)
• Herpes virus infections
• Discomfort around the infusion site. May present with bruising, redness, pain, itching, or swelling

Uncommon(may affect up to 1 in 100 people)

• Severe allergy (anaphylactic reaction)
• Progressive multifocal leukoencephalopathy (PML)
• Inflammatory disorder after stopping the medicine
• Swelling of the face
• Increased number of white blood cells (eosinophilia)
• Reduced number of platelets
• Easy bruising (purpura)

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

• Herpes virus infection in the eye
• Severe anemia (reduced number of red blood cells that can make your skin pale and make you feel short of breath or lacking energy)
• Severe swelling under the skin
• High levels of bilirubin in the blood (hyperbilirubinemia)that can cause symptoms such as yellowing of the eyes or skin, fever, and fatigue

Frequency Not Known(cannot be estimated from the available data)

• Rare infections (so-called “opportunistic infections”)
• Liver damage

Tell your doctor as soon as possibleif you think you have an infection.

You will also find this information on the patient alert card that your doctor has given you.

Reporting of Adverse Effects

If you experience any adverse effect, consult your doctor, even if it is a possible adverse effect that is not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Tyruko

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date that appears on the label and carton. The expiry date is the last day of the month indicated.

Unopened Vial:

Store in a refrigerator. Do not freeze.

Keep the vial in the outer packaging to protect it from light.

Diluted Solution:

It is recommended to use the product immediately after dilution. If not, the diluted solution must be stored between 2°C and 8°C and infused within 24 hours after dilution.

Do not use this medicine if you notice particles or color changes in the liquid.

6. Package Contents and Additional Information

Composition of Tyruko

The active substance is natalizumab. Each 15 ml vial of concentrate contains 300 mg of natalizumab (20 mg/ml). When diluted, the solution for infusion contains approximately 2.6 mg per ml of natalizumab.

The other ingredients are:

Sodium chloride (see section 2 “Tyruko contains sodium”)

Histidine

Monohydrate histidine

Polysorbate 80 (E 433)

Water for injectable preparations

Appearance and Package Contents

Tyruko is a colorless, transparent to slightly opalescent solution (sterile concentrate).

Each carton contains one glass vial.

Marketing Authorization Holder and Manufacturer

Sandoz GmbH

Biochemiestrasse 10

6250 Kundl

Austria

Date of Last Revision of this Leaflet:

Other Sources of Information

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

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This information is intended only for healthcare professionals:

1. Inspect the Tyruko vial for the absence of particles before dilution and administration. If particles are observed or if the liquid is not colorless and transparent to slightly opalescent, the vial must not be used.

1. Use an aseptic technique to prepare the medicine. Remove the flip-off cap from the vial. Insert the needle of the syringe into the vial, through the center of the stopper, and aspirate 15 ml of concentrate for solution for infusion.

1. Add the 15 ml of concentrate for solution for infusion to 100 ml of sodium chloride 9 mg/ml (0.9%) injectable solution. Gently invert the solution to mix completely. Do not shake.

1. Tyruko must not be mixed with other medicines or diluents.

1. Visually inspect the diluted medicine for the absence of particles or color changes before administration. The diluted product must not be used if particles or color changes are observed.

1. The diluted medicine must be used as soon as possible and within 24 hours after dilution. If the diluted medicine is stored between 2°C and 8°C (do not freeze), it must be allowed to reach room temperature before infusion.

1. The diluted solution is intended for intravenous infusion over 1 hour, at an approximate rate of 2 ml per minute.

1. After completion of the infusion, the intravenous infusion lines are flushed with sodium chloride 9 mg/ml (0.9%) injectable solution.

1. The vials are for single use.

1. In order to improve the traceability of biological medicines, the name and batch number of the administered medicine should be clearly recorded.

1. The disposal of unused medicine and all materials that have come into contact with it should be carried out in accordance with local regulations.