Prospect: information for the patient

Tyruko 300mg concentrate for solution for infusion

natalizumab

This medicine is subject to additional monitoring, which will speed up the detection of new information about its safety. You can contribute by reporting any adverse effects you may experience. The final part of section4 includes information on how to report these adverse effects.

Read this prospect carefully before starting to use this medicine, because it contains important information for you.

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

• Keep this prospect and the patient alert card, as you may need to refer to them again. Keep the prospect and the patient alert card with you during treatment and for six months after the last dose of this medicine, as adverse effects may occur even after treatment has been stopped.
• If you have any questions, consult your doctor.
• If you experience adverse effects, consult your doctor, even if they are not listed in this prospect. See section4.

1.What is Tyruko and what it is used for

2.What you need to know before starting to receive Tyruko

3.How Tyruko is administered

4.Possible adverse effects

5.Storage of Tyruko

6.Contents of the package and additional information

Tyruko is used to treat multiple sclerosis (MS). It contains the active ingredient natalizumab. It is known as a monoclonal antibody.

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

Multiple sclerosis symptoms

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

They may include: difficulty walking, tingling in the face, arms, or legs; vision problems; fatigue; sensation of instability or dizziness; urinary and intestinal problems; difficulty thinking and concentrating; depression; acute or chronic pain; sexual problems; muscle stiffness and spasms. When symptoms worsen, it is calledrelapse(also exacerbation or flare-up). When a relapse occurs, you may notice symptoms suddenly, within a few hours, or with a gradual progression over several days. Symptoms generally improve gradually (this is called remission).

How Tyruko can help

In trials, this medication reduced approximately half of the increase in disability caused by MS and reduced the number of MS relapses by approximately two-thirds. While you are taking this medication, you may not notice any improvement but you can continue to act to prevent the worsening of MS.

Before starting treatment with this medication, it is essential that you and your doctor have discussed the beneficial effects you can expect to receive from this treatment and the associated risks.

Do not administer Tyruko

• If you areallergicto natalizumab or any of the other components of this medication (listed in section6).

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

• If yourimmune systemhas a severe problem. This may be due to an illness (such as HIV infection) or medications you are using or have used in the past (see below).

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

• If youhave cancer(except for a type of skin cancer calledbasal cell carcinoma).

Warnings and precautions

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

Possible cerebral infection (PML)

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

• Before starting treatment, your doctor will perform ablood 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 related to 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-JC virus antibodies), which are a sign that you have been infected with the JC virus.

• Your doctor will perform amagnetic resonance imaging (MRI) scan, which will be repeated during treatment to rule out PML.

• PML symptomsmay be similar to those of a relapse of MS (see section4,Adverse reactions). You may also develop PML up to 6months after stopping treatment with Tyruko.

• Inform your doctor as soon as possibleif you notice that your MS is worsening or if you experience any new symptoms while on treatment with Tyruko or up to 6months afterwards.

• Inform your partner or caregiverswhat they should be aware of (also see section4,Adverse reactions). Some symptoms may be difficult to detect on your own, such as mood or behavior changes, confusion, speech and communication difficulties. If you experience any of them,you may need to undergo further tests. Be vigilant for symptoms during the 6months following the interruption of Tyruko.

• Keep the patient alert card that your doctor has given you. Include 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-JC virus antibodiesin your blood. They are a sign that the virus is in your body. You will undergo tests before and during treatment with Tyruko.

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

• If you have taken a medication known asimmunosuppressant, which reduces the activity of your immune system.

The JC virus also causes another conditioncalled NCG by JC virus, which has occurred in some patients receiving treatment with Tyruko. The symptoms of NCG by JC virus are similar to those of PML.

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

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

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

If someone develops PML

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

Be aware of other infections

Other infections distinct from PML can also be severe and may be caused by viruses, bacteria, and other causes.

Inform your doctor or nurse immediatelyif you think you have an infection (also see section4,Adverse reactions).

Changes in blood platelet count

Natalizumab can reduce the number of platelets in the blood, which are responsible for clotting. This can lead to a condition called thrombocytopenia (see section4) by which your blood may not clot quickly enough to stop bleeding. This can cause the appearance of bruises, as well as more serious problems such as excessive bleeding. Inform your doctor immediately if you experience unexplained bruises, red or purple spots on the skin (called petechiae), bleeding that does not stop or oozes from cuts on the skin, 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 administer this medication to children or adolescents under 18years of age.

Other medications and Tyruko

Inform your doctor if you are using, have used recently, or may need to use any other medication.

• Do not administer this medicationif you are currently being treated with medications that affect yourimmune system, including certain medications used to treat MS.

• Itmay be possiblethat you cannot use this medication if you have ever taken any medication that affects the immune system.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor before using this medication.

• Do not use this medication if you are pregnant, unless you have discussed it with your doctor. If you are pregnant, think you may be pregnant, or intend to become pregnant, you must inform your doctor immediately.

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

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

Driving and operating machines

Dizziness is a very common adverse reaction. If you experience this symptom, do not drive or operate machines.

Tyruko contains sodium

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

Tyruko intravenous infusion should be administered to the patient by a doctor experienced in the treatment of EM. Your doctor may change your treatment directly to Tyruko if no problems associated with the previous treatment are observed.

• Your doctor will requestblood teststo detect anti-VJC antibodies and other possible problems.

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

• To change some medications for EM,your doctor may recommend that you wait a certain time to ensure that most of the previous medication has been eliminated from your body.

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

• Tyruko must be diluted before administration. It is administered through a catheter in a vein (intravenous infusion), usually in the arm. Administration requires approximately 1hour.

• At the end of the prospectus, information is provided on how to prepare and administer the medication intended for medical or healthcare professionals.

If you interrupt the treatment with Tyruko

It is essential to continue the administration ofTyruko, especially during the first months of treatment. It is essential that you continue treatment while you and your doctor decide that it is helping you. Patients who received one or two doses ofTyrukoand then made a pause in treatment of three months or more had a higher probability of suffering an allergic reaction upon resuming treatment.

Checking for allergic reactions

Some patients have presented an allergic reaction to this medication. Your doctor may check if allergic reactions occur during infusion and during 1 hour afterwards. See also section4,possible side effects.

If you forgot to use Tyruko

If you did not receive your usual dose of Tyruko, talk to your doctor to have it administered as soon as possible. Then, you can continue receiving Tyruko every four weeks.

Will Tyruko always work?

In some patients receivingTyruko, the body's natural defenses may prevent the medication from working correctly over time as the body produces antibodies against the medication. Your doctor may decide if this medication is not working correctly for you based on your blood test and will interrupt treatment if necessary.

If you have any other doubts about the use ofTyruko, ask your doctor. Follow exactly the medication administration instructions contained in this prospectus or those indicated by your doctor. In case of doubt, ask your doctor.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Inform your doctor or nurse immediatelyif you observe 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
• Stiffness of the neck
• Extreme sensitivity to bright light
• Fever
• Skin rash (anywhere on the body)

These symptoms may be due to a brain infection (encephalitis or LMP) or the covering that surrounds it (meningitis).

Signs of other severe infections

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

Signs of allergic reaction

• Urticaria(hives)
• Swelling of the face, lips, or tongue
• Difficulty breathing
• Pain or discomfort in the chest
• Increased or decreased blood pressure (your doctor or nurse will advise 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 the white of the eyes
• Unusual darkening of the urine
• Abnormal liver function test

If you experience any of the adverse effects described above or if you think you have an infectionconsult 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 10people)

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

Common(may affect 1 in 10people)

• Anemia (decrease in the number of red blood cells that may make your skin pale and feel short of breath or lacking energy)
• Allergy(hypersensitivity)
• Chills
• Urticaria(hives)
• Vomiting
• Fever
• Difficulty breathing(dyspnea)
• Redness of the face or body(flushing)
• Herpes virus infections
• Discomfort around the site where the infusion was administered. You may experience bruising, redness, pain, itching, or swelling

Rare(may affect up to 1 in 1000people)

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

Frequency not known(cannot be estimated from available data)

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

Inform 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 adverse effects

If you experience any type of adverse effect, consult your doctor, even if it is a possible adverse effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the label and the box. The expiration date is the last day of the month indicated.

Unopened vial:

Store in the refrigerator. Do not freeze.

Store 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 be infused within a maximum of 24hours after dilution.

Do not use this medication if you observe particles or color changes in the liquid.

Composition of Tyruko

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

The other components are:

Sodium chloride(see section2 “Tyruko contains sodium”)

Histidine

Monohistidine chloride

Polysorbate80(E433)

Water for injection

Appearance of the product and contents of the package

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

Each carton package contains a glass vial.

Marketing authorization holder and responsible manufacturer

Sandoz GmbH

Biochemiestrasse 10

6250 Kundl

Austria

Last review date of this leaflet:

Other sources of information

The 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 solely for healthcare professionals:

1. Inspect the Tyruko vial to check 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 should not be used.

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

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

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

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

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

1. The diluted solution is intended to be infused intravenously over 1 hour, at an approximate rate of 2ml per minute.

1. After infusion, the intravenous infusion tubes are washed with sodium chloride 9mg/ml (0.9%) injection 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.