Package Insert: Information for the Patient

Tysabri 150mg injectable solution in pre-filled syringe

Natalizumab

Read this package insert carefully before starting to use this medication, because it contains important information for you.

In addition to this package insert, you will be given a patient information leaflet. This contains important safety information that you should know before receiving and during treatment with Tysabri.

• Keep this package insert and the patient information leaflet, as you may need to refer to them again. Keep the package insert and the patient information leaflet with you during treatment and for six months after the last dose of this medication, as adverse effects may occur even after treatment has been discontinued.

• If you have any questions, consult your doctor.
• If you experience any adverse effects, consult your doctor, even if they are not listed in this package insert.See section4.

TYSABRI is used to treat multiple sclerosis (MS). It contains the active ingredient natalizumab. It is known as amonoclonal 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.

MS symptoms

MS symptoms 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; feeling unsteady or dizzy; urinary and intestinal problems; difficulty thinking and concentrating; depression; acute or chronic pain; sexual problems; muscle stiffness and spasms.

When symptoms worsen, it is called arelapse(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 aremission).

How Tysabri can help

In studies, this medication reduced approximately half 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 it may continue to act to prevent MS from worsening.

Before starting treatment with this medicine, 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 Tysabri

• If you are allergic to 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 Tysabri.

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

Warnings and precautions

Consult your doctorif Tysabri is the most suitable treatment for you. Do this before starting to use this medication 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 Tysabri 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 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,possible side effects). You may also develop PML up to 6months after stopping Tysabri treatment.

Inform your doctor as soon as possibleif you notice that your MS is worsening or if you notice any new symptoms while on Tysabri treatment or up to 6months after.

• Inform your partner or caregiverswhat they should be aware of (also see section4,possible side effects). 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 these, it is possible that you will need to undergo further tests.

• Keep the patient information 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 Tysabri. If you have two or more of these risk factors, the risk increases even more:

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

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

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

The JC virus also causes another conditioncalled NCG by JC virus(granular cell neuronopathy by JC virus) that has occurred in some patients receiving this medication. The symptoms of NCG by JC virus are similar to those of PML.

For patients with lower PML risk, it may be possible for your doctor to repeat the tests periodically to check:

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

• If you have received treatment for more than 2years, if you still have a lower level ofanti-JCantibodies in your blood.

If someone develops PML

PML can be treated, and Tysabri treatment will be interrupted. However, some peopleexperience a reactionwhen Tysabri is eliminated from the body. This reaction (known asSIRIorimmune reconstitution inflammatory syndrome) can make your condition worse, including a decline in brain function.

Be aware of other infections

Other infections that are not 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,possible side effects).

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 section 4) 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 Tysabri

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, such as certain medications used to treat MS.

• You may not be able to use this medication if you have ever taken any medication that affects the immune system.

Pregnancy and breastfeeding

• 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, inform your doctor immediately.

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

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

Tysabri contains sodium

This medication contains less than 1mmol of sodium (23mg) per 300mg dose; it is essentially “sodium-free”.

Tysabri injections will be prescribed by a doctor experienced in treating MS. Your doctor may switch you directly from another medication to Tysabri if there are no signs of problems caused by the previous treatment.Tysabri injections will be administered by a healthcare professional.

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

• If your condition allows, your doctor may discuss with you the possibility of receiving injections outside a hospital setting (e.g., at home).

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

• Each dose is administered intwo injectionsunder the skin, in the thigh, abdomen, or the back of the arm. Administration requires up to 30minutes.

• Information on how to prepare and inject the medication is provided at the end of the leaflet for healthcare professionals or medical staff.

If you interrupt treatment with Tysabri

Continuous administration of Tysabri is important, especially during the first few 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 of Tysabri and then paused treatment for three months or more had a higher probability of experiencing an allergic reaction upon resuming treatment.

Checking for allergic reactions

Some patients have presented an allergic reaction to this medication. Your doctor will check for allergic reactions during injections and within 1hour afterwards. See section4,Possible side effects.

If you forgot to use Tysabri

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

Will Tysabri always work?

In some patients receiving Tysabri, 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 that this medication is not working correctly based on your blood test and will stop treatment if necessary.

If you have any other questions about using Tysabri, ask your doctor.Follow exactly the medication administration instructions contained in this leaflet or those indicated by your doctor. In case of doubt, ask your doctor.

Subcutaneous is abbreviated as SC on the syringe label.

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
• Neck stiffness
• 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
• Chest pain or discomfort
• 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 the injection.

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 side effects described above or if you think you have an infectionconsult your doctor or nurse immediately. Show your patient information cardand this leaflet to any doctor or nurse who treats you, not just your neurologist.

Other side effects

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

• Urinary tract infection
• Sore throat and congestion or nasal discharge
• Headache
• Dizziness
• Unpleasant feeling(nausea)
• Joint pain
• Fatigue

Common(may affect 1 in 10 people)

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

Rare(may affect up to 1 in 1000 people)

• 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 tired)
• 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 unknown(cannot be estimated from available data)

• Rare infections of the brain and eyes
• Liver damage

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

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

Reporting side effects

If you experienceany type of side effect, consult your doctor, even if it is apossibleside effect that does not appear in this leaflet.You can also report them directly throughthenational reporting system included in theAppendix V.By reporting side effects, you can contribute to providing more information about 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.

Store in refrigerator.(between 2 °C and 8 °C).

Do not freeze.

Store the syringes in the outer packaging to protect them from light.

Pre-filled syringes can be stored at room temperature (up to 30 °C) for a maximum combined time of up to 24 hours, including the time necessary for them to reach room temperature for administration. The syringes can be returned to the refrigerator and used before the expiration date indicated on the label and the box. The date and time the container is removed from the refrigerator should be noted on the box. Discard the syringes if they are left out of the refrigerator for more than 24 hours. Do not use external heat sources, such as hot water, to warm pre-filled syringes.

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

Composition of Tysabri

The active ingredient is natalizumab.

Each pre-filled syringe of 1ml contains 150mg of natalizumab.

The other components are:

Sodium monobasic phosphate monohydrate

Dibasic sodium phosphate heptahydrate

Sodium chloride (see section2 “Tysabri contains sodium”)

Polysorbate 80(E433)

Water for injection

Appearance of the product and contents of the pack

Tysabri is a colourless to slightly yellowish and slightly opalescent to opalescent liquid.

Each pack contains two syringes.

Tysabri is available in packs containing 2syringes pre-filled.

Marketing authorisation holder and manufacturer

Biogen Netherlands B.V.

Prins Mauritslaan 13

1171 LP Badhoevedorp

Netherlands

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

Last update of this leaflet:

Other sources of information

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

--------------------------------------------------------------------------------------------------------------------

This information is intended for healthcare professionals only:

Before administering the subcutaneous injection of Tysabri outside a hospital setting, the healthcare professional must complete the Out-of-Hospital Administration Checklist for each patient, before each administration, to ensure that the injection can be administered.

The recommended dose of 300mg should be administered with two pre-filled syringes of 150mg, see section3 below.

Administration instructions

The pre-filled syringe has an automatic needle protection system that will activate when the plunger is fully pressed. When releasing the plunger, the needle protector will cover the exposed needle.

1. Remove the pack containing the dose from the refrigerator and let it come to room temperature (up to 25°C) before administering the injections. The recommended time for warming up is 30minutes.

The date and time the pack was removed from the refrigerator must be recorded in the box.

• Do not use external heat sources, such as hot water, to warm the pre-filled syringes.
• Do not touch or re-cap the needle at any time to avoid accidental needlestick injuries.

2.Remove both product syringes from the tray. Check that the medication in each pre-filled syringe is a colourless to slightly yellowish and slightly opalescent liquid and does not contain visible particles. You may see air bubbles in the viewing windows. This is normal and will not affect the dose.

• Check bothpre-filled syringes. Do not use them if:
• • The expiry date marked on the syringe label has passed (EXP).

or

• Si observa algo de lo mencionado anteriormente, póngase en contacto con su farmaciainmediatamente.

3. A complete dose is equivalent to two consecutive injections with a 30minute interval between them.

4. Use an aseptic technique (clean and germ-free) and a flat work surface during the injection procedure.

5. Choose the first subcutaneous injection site in the thigh, abdomen, or upper arm.

6. Administer the first injection.

7. Push the plunger slowly with a smooth motion until the syringe is completely empty. Do not pull the plunger.

8. Before removing the syringe, check that it is empty. If you see any blood, press with a cotton swab or gauze on the area. Do not rub the skin after administering the injection. When removing the syringe from the injection site, release the plunger WHILE pulling the needle out. When releasing the plunger, the needle protector will cover the exposed needle.

9. Administer the injections one after the other without significant delays. In the case where the second injection cannot be administered immediately after the first injection, the second injection must be administered at the latest 30minutes after the first injection. The second injection must be at least 3cm away from the site of the first injection.

Patientsmust be kept under observation during the administration of subcutaneous injections and for the hour followingto detect any signs and symptoms of reactions at the injection site, including hypersensitivity. After the first 6doses of Tysabri,regardless of the route of administration, patients must be kept under observation after subcutaneous injection administration according to clinical judgment.

Stop administering the injection immediately upon observing any sign or symptom compatible with an allergic reaction [see section4.4 of the SmPC].

10. Dispose of the used syringe in accordance with local regulations.