Consumer medicine information

Tysabri

Natalizumab

BRAND INFORMATION

Brand name

Tysabri

Active ingredient

Natalizumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tysabri.

SUMMARY CMI

TYSABRI®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using TYSABRI?

TYSABRI contains the active ingredient natalizumab. TYSABRI is used to treat relapsing remitting Multiple Sclerosis (MS).

For more information, see Section 1. Why am I using TYSABRI? in the full CMI.

2. What should I know before I use TYSABRI?

Do not use if you have ever had an allergic reaction to Tysabri or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use TYSABRI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TYSABRI and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TYSABRI?

  • The recommended dose of TYSABRI is 300 mg given once every 4 weeks.
  • TYSABRI will be prepared and given to you by a doctor or nurse.

More instructions can be found in Section 4. How do I use TYSABRI? in the full CMI.

5. What should I know while using TYSABRI?

Things you should do
  • Remind any doctor, dentist, nurse or pharmacist you visit that you are using Tysabri.
  • Call your doctor straight away if you or your partner or caregiver notice any new or worsening medical problems (fever or infection, new or sudden change in your thinking, eyesight, balance or strength)
Things you should not do
  • Do not stop using this medicine without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how TYSABRI affects you.
  • TYSABRI may cause dizziness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep TYSABRI in the refrigerator at 2°C to 8°C.
  • TYSABRI must not be frozen.
  • Keep TYSABRI in the pack until it is time to use it.

For more information, see Section 5. What should I know while using TYSABRI? in the full CMI.

6. Are there any side effects?

Common side effects include: sore throat, runny nose, nausea or vomiting, pain or stinging when passing urine, shivering, itch, headache, dizziness, tiredness, joint pain or fever.

Serious side effects include: infections, jaundice, anaemia, allergy or infection in the brain.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: TYSABRI may increase your chance of getting a rare viral brain infection called progressive multifocal leukoencephalopathy (PML) that may lead to death or severe disability. Your doctor will perform tests to assess your risk of getting PML before giving you TYSABRI. You should also be closely monitored for signs and symptoms of PML while you are taking TYSABRI.



FULL CMI

TYSABRI® (tie-SA-bree)

Active ingredient(s): Natalizumab (nat-ah-li-zoo-mab)

Consumer Medicine Information (CMI)

This leaflet provides important information about using TYSABRI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TYSABRI.

Where to find information in this leaflet:

1. Why am I using TYSABRI?
2. What should I know before I use TYSABRI?
3. What if I am taking other medicines?
4. How do I use TYSABRI?
5. What should I know while using TYSABRI?
6. Are there any side effects?
7. Product details

1. Why am I using TYSABRI?

TYSABRI contains the active ingredient natalizumab. TYSABRI is a type of protein used to treat relapsing remitting Multiple Sclerosis (MS).

The cause of MS is not yet known. MS affects the brain and spinal cord. In MS, the body's immune system reacts against its own myelin (the 'insulation' surrounding nerve fibres). In relapsing remitting MS, people have 'exacerbations' from time to time (e.g. blurred vision, weakness in the legs or arms, or loss of control of bowel or bladder function).

These are followed by periods of recovery. Recovery may be complete or incomplete. If it is incomplete there is 'progression of disability'.

TYSABRI decreases the inflammation in your brain that is caused by Multiple Sclerosis (MS) and thereby reduces nerve damage.

TYSABRI works by binding to white blood cells and preventing them from moving into the brain and spinal cord where they cause inflammation, an important part of the MS disease process.

TYSABRI slows down the progression of physical disability in people with relapsing remitting MS and decreases the number of flare-ups (relapses). Some people feel better when they start to take TYSABRI. However, TYSABRI cannot repair damage that has already been caused by MS.

When you start on TYSABRI you might not notice any improvement, but TYSABRI may be working to help prevent your MS from becoming worse.

TYSABRI has not been tested in clinical trials in people with MS who are 65 years and over. TYSABRI has not been studied in patients with chronic progressive MS.

Your doctor, however, may prescribe TYSABRI for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you.

There is not enough information to recommend this medicine for children or adolescents under 18 years of age or elderly 65 years and over.

2. What should I know before I use TYSABRI?

Warnings

Do not use TYSABRI if you:

  • are allergic to natalizumab, or any of the ingredients listed at the end of this leaflet.
  • are allergic to any other proteins that are of mouse origin.
    Always check the ingredients to make sure you can use this medicine.
    Symptoms of allergic reactions may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.
  • have or have had PML (progressive multifocal leukoencephalopathy). PML is a rare viral infection of the brain.
  • have suppressed immune function, e.g. due to:
    - a medical condition, such as HIV-AIDS, organ transplant or cancer
    - medicines that affect the immune system.
  • are taking medicines that modify the activity of the immune system e.g. an interferon or glatiramer acetate.

TYSABRI must not be used after the expiry date, if there are particles in the solution, or if it is discoloured or cloudy.

If you are not sure whether you should use this medicine, talk to your doctor, nurse or pharmacist.

Check with your doctor if you have or have had:

  • allergies to any other medicines, foods, preservatives or dyes
  • an infusion or injection reaction with any other medicine
  • liver problems
  • previous treatment with TYSABRI.

You will need a recent brain scan (MRI) (within 3 months) before you start treatment with TYSABRI.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Your doctor will discuss the risks and benefits of using TYSABRI if you are pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

TYSABRI passes into the breast milk. Your doctor will discuss the risks and benefits of using it if you are breast-feeding or planning to breast-feed.

Patient alert card

Your doctor will give you a Patient Alert Card to keep with you, which summarises the most important information from this leaflet.

Keep this leaflet and the Patient Alert Card with you during treatment and for at least 6 months after your last dose, as side effects can occur after you have stopped treatment.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are being treated or have previously been treated with any medicine that affects immune function.

Examples of such medicines may include:

  • medicines used for autoimmune diseases or after organ transplant, e.g. azathioprine
  • cancer drugs, such as mitoxantrone
  • steroids, e.g. for asthma, arthritis or skin disease.

You may not be able to take some medicines that affect your immune system at the same time as having treatment with TYSABRI.

  • There are many medicines that can affect immune function. It is a good idea to keep a list of your medicines and take it with you when you go to your doctor or treatment centre.

Check with your doctor, nurse or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TYSABRI.

4. How do I use TYSABRI?

How much to use

  • The recommended dose of TYSABRI is 300 mg given once every 4 weeks.
  • Follow all directions given to you by your doctor, nurse or pharmacist carefully.
    They may differ from the information contained in this leaflet.

When to use TYSABRI

  • TYSABRI is given once every 4 weeks.

How to use TYSABRI

  • TYSABRI will be prepared and given to you by a doctor or nurse.
  • TYSABRI for infusion will be diluted before it is given to you. It is given as a drip through a needle placed into a vein (IV infusion), usually in your arm. This takes about 1 hour.
  • TYSABRI injection in prefilled syringes requires no preparation. It is given as two injections just under the skin of your thigh, abdomen or upper arm.
  • A few patients have had an allergic reaction to TYSABRI. Your doctor or nurse will check for allergic reactions during the infusion or injection and for 1 hour afterwards.
  • Infusion with TYSABRI should start as soon as possible after the medicine has been diluted. If not used immediately, the solution must be stored at 2°C to 8°C and infused within 72 hours of dilution.
  • The prefilled syringes can be kept in their original packaging for up to 24 hours at room temperature. The prefilled syringe should not be returned to refrigeration. Do not use external heat sources, such as hot water, to warm the prefilled syringe.

The positive effects of TYSABRI may not be seen immediately.

They occur with long-term treatment. It is important to continue treatment with TYSABRI unless your doctor tells you to stop.

Do not interrupt your treatment, especially during the first few months. Patients who received up to 3 doses of TYSABRI followed by a gap in treatment of 3 months or more, were more likely to have an allergic reaction when restarting treatment.

Your doctor will discuss with you the benefits and risks of continuing treatment after 2 years.

If you forget to use TYSABRI

TYSABRI is given once every 4 weeks. If you miss one of your treatments, you should have it as soon as possible, unless your doctor has told you otherwise. Then resume your regular monthly schedule.

If you use too much TYSABRI

As TYSABRI is given to you under the supervision of a doctor or nurse, it is unlikely that you will receive too much.

Nevertheless, if you think that you have been given too much TYSABRI, you may need urgent medical attention.

You should immediately:

  • phone the Australian Poisons Information Centre
    (by calling 13 11 26), or the New Zealand National Poisons Information Centre (by calling 0800 POISON or 0800 764 766), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using TYSABRI?

Things you should do

Call your doctor straight away if you:

  • if you notice any new or worsening medical problems (fever or infection, new or sudden change in your thinking, eyesight, balance or strength) that have lasted several days.
  • Tell your partner or caregiver about your treatment.

Ask them to tell your doctor immediately if they notice any changes in you, such as a new or sudden change in your personality, thinking abilities or any unusual behaviour.

When possible, encourage your partner or caregiver to go with you to see your doctor and to the centre for your treatments.

PML and TYSABRI

TYSABRI increases your chance of getting a rare viral brain infection called progressive multifocal leukoencephalopathy (PML) that can cause severe disability or be life-threatening.

Your chance of getting PML increases if you have been exposed to John Cunningham Virus (JCV). Approximately half of all people have been exposed to JCV. JCV is a common virus that is harmless in most people but can cause PML in people who have weakened immune systems, such as people taking TYSABRI. Most people have been exposed to JCV without knowing it or having any symptoms. This exposure usually happens in childhood.

Your doctor should test your blood to check if you have antibodies to the JC virus before treatment and periodically during treatment.

The risk of developing PML whilst on TYSABRI is higher:

  • If you have antibodies to the JC virus in your blood. These antibodies are a sign that you have been infected by JC virus.
  • The longer you are on treatment, especially if you have been on treatment for more than two years.
  • If you have previously taken a medicine called an immunosuppressant. These medicines reduce the activity of your body's immune system.

Your risk of getting PML is greatest if you have all 3 risk factors listed above.

If you have not previously been treated with an immunosuppressant and you have received TYSABRI for two years or longer, the level of your anti-JC virus antibody test results may help your doctor assess your risk of getting PML. Your doctor may repeat the test regularly to check if anything has changed:

  • if you do not have antibodies to the JC virus in your blood
    OR
  • if you have been treated for more than 2 years and you have a lower level of JCV antibodies in your blood.

You should discuss with your doctor if TYSABRI is the most suitable treatment for you before you start treatment and when you have been taking TYSABRI for more than two years if you have antibodies to the JC virus in your blood.

Some of the symptoms of PML are similar to MS. If you believe your MS is getting worse or if you notice new symptoms while you are on TYSABRI treatment or for up to 6 months after stopping TYSABRI, it is important to speak to your doctor as soon as possible.

If you have new symptoms, or an infection, that last or worsen over several days, contact your doctor before you go for your next treatment.

In some cases, you may not be able to have your treatment without first seeing your doctor. They will be able to tell you if this is necessary.

If your doctor suspects PML, they will want you to stop treatment with TYSABRI either permanently or until they can confirm it is not PML.

Management of patients with PML may require removal of TYSABRI from the blood, usually by plasma exchange. This may lead to further serious complications, including worsening of brain (neurological) function. Your doctor will monitor you for this.

Keep all your doctor's appointments so that your progress can be checked.

Your doctor will need to see you 3 months after your first treatment, 6 months after your first treatment and every 6 months after that. They may also need to see you between routine check-ups if you have had liver problems or in the case of some side effects. Your doctor may also perform regular brain scans (MRI) to check the progress of your MS and if you have a higher chance of getting PML.

If you become pregnant while on treatment with TYSABRI, immediately tell your doctor.

Your doctor will discuss the risks and benefits of being given TYSABRI if you become pregnant.

Tell any other doctors, dentists and pharmacists who treat you that you are using this medicine.

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are using or have used TYSABRI. Tell your doctor if you are going to be vaccinated.

TYSABRI may have effects for about 12 weeks after the last dose. Any new medicine you start during this time might be affected by your previous treatment with TYSABRI.

If you are about to have any blood tests, tell your doctor that you are using or have used TYSABRI.

It may interfere with the results of some tests.

Things you should not do

  • Do not stop using this medicine without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TYSABRI affects you.

There are no studies of the effect of TYSABRI on your ability to drive or to operate machinery but TYSABRI may cause dizziness in some people. Make sure you know how you react to TYSABRI before you do anything that could be dangerous if you are dizzy.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep TYSABRI in the pack until it is time to use it.
  • This medicine will not keep as well if taken out of the packaging.
  • Keep TYSABRI in the refrigerator at 2°C to 8°C.
  • TYSABRI must not be frozen. Do not place in the freezer or freezing compartment of a refrigerator.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

Each vial or prefilled syringe of TYSABRI should be used once only. The doctor or nurse will discard any unused portion.

6. Are there any side effects?

TYSABRI helps most people with MS but it may have unwanted effects in a few people. All medicines have side effects. Sometimes they are serious, most of the time they are not.

See the information below and, if you need to, ask your doctor, nurse or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Respiratory-related:
  • sore throat
  • runny or blocked nose
Digestion system-related:
  • feeling sick (nausea)
  • being sick (vomiting)
Urine system-related:
  • pain or stinging when passing urine
Nervous system-related:
  • headache
  • dizziness
  • tiredness
Non-specific effect on the body:
  • shivering
  • itchy rash (hives)
  • joint pain
  • fever
Speak to your doctor if you have any of these less serious side effects and they worry you.
If any of these side effects persist or worsen, talk to your doctor as they may also be due to an infection or allergic reaction.

Serious side effects

Serious side effectsWhat to do
Infection-related:
  • unexplained fever, severe diarrhoea, prolonged dizziness, headache or stiff neck, weight loss, listlessness, impaired vision, pain or redness of the eye(s)
Liver-related:
  • yellowing of the skin or eyes (also called jaundice)
Blood-related:
  • tiredness, headaches, shortness of breath when exercising, dizziness, or looking pale, which may be signs of severe anaemia due to a decrease in red blood cells.
Allergic reaction-related:
  • itchy rash or hives
  • swelling of your face, lips, tongue or other parts of the body
  • shortness of breath, wheezing, difficulty breathing, chest pain or discomfort.
These can be signs of very serious side effects. If you have them, you may have had a serious allergic reaction to TYSABRI.
Serious infection of the brain related:
  • psychological or intellectual changes such as changes in personality and behaviour, difficulty performing mental tasks, confusion, delirium or loss of consciousness, seizures (fits), headache, nausea / vomiting, stiff neck, extreme sensitivity to bright light, fever, rash.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Serious side effects are rare.

There have been reports of a rare brain infection called PML (progressive multifocal leukoencephalopathy) occurring in patients who have been given TYSABRI.

PML is a serious condition and can cause severe disability or be life-threatening.

Some of the symptoms of PML are similar to MS, so it is important that you speak to your doctor as soon as possible if you notice any new symptoms, or if your MS gets worse (see the 'PML and TYSABRI' section of this CMI).

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What TYSABRI contains

Each vial of TYSABRI for infusion contains 300 mg natalizumab in 15 mL of solution.

Each prefilled syringe of TYSABRI for subcutaneous injection contains 150 mg natalizumab in 1 mL of solution.

Active ingredient
(main ingredient)		Natalizumab
Other ingredients
(inactive ingredients)		sodium chloride
monobasic sodium phosphate monohydrate
dibasic sodium phosphate heptahydrate
polysorbate 80
water for injections.
Potential allergensNone

Do not take this medicine if you are allergic to any of these ingredients.

TYSABRI does not contain any preservative.

What TYSABRI looks like

Each pack of TYSABRI for infusion contains one vial of TYSABRI. TYSABRI for infusion is a colourless, clear to slightly opalescent, concentrated solution for infusion.

Each pack of TYSABRI for subcutaneous injection contains two prefilled syringes of TYSABRI.

TYSABRI for subcutaneous injection is a colourless to slightly yellow, slightly opalescent to opalescent solution for injection.*

Australian Register Number:

AUST R 112372 (concentrated solution for infusion)

AUST R 353845 (solution for subcutaneous injection)*

Further information

You can obtain more information from your doctor, pharmacist or the MS Society in your State, or by telephoning 1800 852 289 in Australia or 0800 852 289 in NZ.

Who distributes TYSABRI

TYSABRI is supplied in Australia by:

Biogen Australia Pty Ltd
ABN 30 095 760 115
Level 4, 2 Banfield Road
Macquarie Park NSW 2113
Australia

TYSABRI is supplied in New Zealand by:

Biogen NZ Biopharma Limited
Auckland, New Zealand

This leaflet was prepared in November 2023

* Not currently marketed.

TYSABRI and BIOGEN are registered trademarks of Biogen MA Inc.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Tysabri

Active ingredient

Natalizumab

Schedule

S4

 

1 Name of Medicine

Natalizumab.

2 Qualitative and Quantitative Composition

Concentrated solution for intravenous infusion.

Each 15 mL dose contains 300 mg natalizumab. The formulation also contains sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, polysorbate 80 and water for injections, at pH 6.1.

Subcutaneous injection*.

Each dose contains 300 mg natalizumab (two injections of 150 mg/1 mL prefilled syringes). The formulation also contains sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate and polysorbate 80 and water for injections, at pH 6.0.
Tysabri (natalizumab) is a recombinant humanised IgG4 monoclonal antibody produced in murine myeloma cells. Natalizumab (rmc) contains human framework regions and the complementarity determining regions of a murine antibody that binds to α4-integrin. The molecular weight of natalizumab is 149 kilodaltons.
* Not currently marketed.

3 Pharmaceutical Form

Tysabri (natalizumab) concentrate for intravenous infusion is supplied as a sterile, colourless, clear to slightly opalescent solution.
Tysabri (natalizumab) for subcutaneous injection is a sterile, colourless to slightly yellow, slightly opalescent to opalescent solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Tysabri is indicated as monotherapy for the treatment of patients with relapsing remitting multiple sclerosis (MS) to delay the progression of physical disability and to reduce the frequency of relapse.

4.2 Dose and Method of Administration

Tysabri therapy is to be initiated and supervised by neurologists, with timely access to MRI. Administration is to be performed by a healthcare professional and patients are to be monitored for early signs and symptoms of PML.
Tysabri intravenous formulation is not intended for subcutaneous administration and vice versa.

Adults.

Intravenous dosing regimen.

The recommended dose of Tysabri by intravenous infusion is 300 mg every four weeks. Dilute Tysabri concentrate 300 mg/15 mL in 100 mL 0.9% sodium chloride, and infuse over approximately one hour. Do not administer Tysabri as an intravenous push or bolus injection (see Preparation instructions).
Observe patients during the infusion and for 1 hour after the infusion is complete. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity type reaction (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity). Staff and facilities should be available for treating anaphylaxis, in the unlikely event that this occurs. After the first 12 intravenous Tysabri doses, patients should continue to be observed during infusion and observed after infusion according to clinical judgment.

Subcutaneous dosing regimen.

The recommended dose of Tysabri for subcutaneous injection is 300 mg every 4 weeks. Administer injections one after the other without significant delay. The second injection should be administered no later than 30 minutes after the first injection. Patients should be observed during both subcutaneous injections and for 1 hour after for signs and symptoms of injection reactions including hypersensitivity. After the first 6 Tysabri doses, regardless of route of administration, patients should be observed after subcutaneous injection according to clinical judgment. If none of the first 6 doses were subcutaneous, patients should be observed for 1 hour after the first subcutaneous dose for signs and symptoms of injection reactions including hypersensitivity.

Switching route of administration.

Any switch in route of administration of Tysabri should be made 4 weeks after the previous dose of Tysabri.

Children and adolescents (< 18 years).

Safety and effectiveness of natalizumab in MS patients below the age of 18 years of age have not been established. No recommendation on dosage can be made. Currently available data are described in Adverse Effects (Undesirable Effects) and Pharmacodynamic Properties, Clinical trials.

Renal and hepatic impairment.

No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment. The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in patients with renal or hepatic impairment.

Monitoring advice.

The information provided in Figure 1 is a graphical summary of guidance provided in Special Warnings and Precautions for Use of the Tysabri product information (PI) concerning patient monitoring, which is provided for information only and should not be used to make clinical decisions. It is important to refer to the full text in the PI to inform individual clinical decisions.

Preparation instructions.

Intravenous dosing regimen.

Tysabri (natalizumab) is free of preservatives. Use aseptic technique when preparing Tysabri solution for intravenous infusion. Tysabri is for single use in one patient only. Discard any residue.
Tysabri is a colourless, clear to slightly opalescent concentrate. Inspect the vial for particulate material prior to dilution and administration. If visible particulates are observed and/or the liquid in the vial is discoloured, the vial must not be used. Do not use Tysabri beyond the expiration date on the carton or vial.
To prepare the solution, withdraw 15 mL of Tysabri concentrate from the vial using a sterile needle and syringe. Inject the concentrate into 100 mL 0.9% sodium chloride. No other intravenous diluents may be used to prepare the Tysabri solution.
Gently invert the Tysabri solution to mix completely. Do not shake. Inspect for particulate material prior to administration.
Following dilution, infuse Tysabri solution immediately or within 72 hours if stored at 2°C to 8°C and protected from light. If stored at 2°C to 8°C, allow the solution to warm to room temperature prior to infusion. Do not freeze.

Subcutaneous dosing regimen.

There is no dilution required with Tysabri for subcutaneous injection.

Administration instructions.

Intravenous infusion.

Infuse Tysabri 300 mg in 100 mL 0.9% sodium chloride over approximately one hour. After the infusion is complete, flush with 0.9% sodium chloride.
Use of filtration devices during administration has not been evaluated. Other medications should not be injected into infusion set side ports or mixed with Tysabri.

Subcutaneous injection.

The sites for subcutaneous injection should be the thigh, abdomen, or the posterior aspect of the upper arm. Do not inject into an area of the body where the skin is irritated, reddened, bruised, infected, or scarred in any way. When removing the syringe from the injection site, let go of the plunger while pulling the needle straight out. Letting go of the plunger will allow the needle guard to extend and cover the needle. The second injection should be at least 2.5 cm away from the first injection location.

4.3 Contraindications

Tysabri should not be administered to patients with known hypersensitivity to natalizumab or any of the excipients, or to patients with known hypersensitivity to murine derived proteins.
Tysabri is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy.
Tysabri should not be administered to patients with increased risk for opportunistic infections, including those immunocompromised due to current or recent immunosuppressive therapies (e.g. azathioprine, mitoxantrone), or systemic medical conditions resulting in significantly compromised immune system function (e.g. human immunodeficiency virus, organ transplant, active malignancy).
Tysabri should not be administered in combination with immunomodulatory agents (e.g. beta-interferons or glatiramer acetate).

4.4 Special Warnings and Precautions for Use

Progressive multifocal leukoencephalopathy.

Use of Tysabri has been associated with an increased risk of PML, an opportunistic infection caused by John Cunningham virus (JCV), which may be fatal or result in severe disability (see Boxed Warnings). There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. Early diagnosis (from clinical and MRI monitoring), and stopping therapy are important factors in management of PML in patients on Tysabri. Tysabri therapy is to be initiated and supervised by neurologists, with timely access to MRI. Prescribing neurologists must discuss the benefits and risks of Tysabri therapy with the patient, and provide them with the Consumer Medicine Information and a Patient Alert Card. After 2 years of treatment, patients should be re-informed about the risks, especially the increased risk of PML, and should be instructed together with their caregivers on early signs and symptoms of PML.
The Patient Alert Card reminds patients that because of the risks of PML and opportunistic infections with Tysabri, they must contact their doctor if they have unusual or prolonged new neurological symptoms or if they have severe or prolonged symptoms of infection. Patients should be instructed that they should inform all their healthcare providers that they are receiving treatment with Tysabri.
The neurologist should re-evaluate the patient 3 months after the first administration, 6 months after the first administration and every 6 months thereafter. Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic benefit beyond 6 months.
PML has been reported following discontinuation of Tysabri in patients who did not have findings suggestive of PML at the time of discontinuation. Patients and healthcare professionals should continue to be vigilant for any new signs or symptoms that may be suggestive of PML for approximately 6 months following discontinuation of Tysabri.
The following risk factors are associated with an increased risk of developing PML:
The presence of anti-JCV antibodies.
Treatment duration, especially beyond 2 years in patients who are anti-JCV antibody positive.
Immunosuppressant use prior to receiving Tysabri.

Detection of PML.

Patients should be instructed, together with their caregivers, on early signs and symptoms of PML. Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of. Patients must be monitored at regular intervals to allow for early detection of any new or worsening neurological symptoms or signs that may be suggestive of PML. The treating clinician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive or psychiatric symptoms).
If new neurological symptoms suggestive of PML occur, further dosing must be suspended immediately until PML has been excluded. PML should be considered as a differential diagnosis in any MS patient taking Tysabri presenting with neurological symptoms and/or new brain lesions on MRI. If any doubt exists, further evaluation, including MRI scan (compared with pretreatment and routine MRI), CSF testing for JC viral DNA and repeat neurological assessments, should be considered. If initial investigations prove negative, but clinical suspicion for PML still remains, Tysabri should not be restarted and repeat investigations should be undertaken. Once the treating clinician has excluded PML, dosing of Tysabri may resume.
If a patient develops PML, the dosing of Tysabri must be permanently discontinued to enable reconstitution of the immune system.

MRI screening for PML.

Before initiation of treatment with Tysabri, a recent (usually within 3 months) magnetic resonance image (MRI) should be available as a reference, and be routinely repeated at least yearly to update this reference. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML.
More frequent MRI monitoring, such as every 3-6 months, should be considered for patients at higher risk of PML. This includes:
patients who have all three risk factors for PML;
patients with anti-JCV antibody index value of greater than 1.5 without prior history of immunosuppressant therapy and more than 2 years of natalizumab treatment.
PML in the absence of symptoms can be detected on MRI and must be confirmed by the presence of JCV DNA in CSF or brain biopsy.

Anti-JCV antibody testing.

Serum anti-JCV antibody testing provides supportive information for risk stratification for PML in patients treated with Tysabri. Therefore, testing should be carried out prior to initiating Tysabri therapy or in patients already receiving Tysabri in whom antibody status is unknown. In addition, anti-JCV antibody testing is recommended for patients with anti-JCV antibody negative status and for those anti-JCV antibody positive patients with lower index value, since the antibody status or index value may change. Anti-JCV antibody negative patients may still be at risk of PML for reasons such as a new JCV infection, fluctuating antibody status or a false negative test result. Therefore six monthly testing of patients who are anti-JCV antibody negative is recommended. Patients with lower index values who have not had prior immunosuppressant use should also be retested periodically, for example every six months, once they reach the two year treatment point to inform on appropriate MRI monitoring.
Testing should be performed using an anti-JCV antibody assay that has been analytically validated in MS patients. Based on a phase 4 study examining longitudinal antibody status over 18 months, there was approximately an 11% annual change in serostatus from anti-JCV antibody negative to positive.
Anti-JCV antibody assays should not be used to diagnose PML.
Use of plasmapheresis (plasma exchange, PLEX) or intravenous immunoglobulin (IVIG) can affect meaningful interpretation of serum anti-JCV antibody testing. Patients should not be tested for anti-JCV antibodies during or within 2 weeks of PLEX due to removal of antibodies from the serum, or within 6 months of IVIG (6 months being 5x half-life for immunoglobulins).

Estimates of PML risk.

The PML risk estimates algorithm (Figure 2) summarises PML risk by anti-JCV antibody status, prior immunosuppressant use and duration of treatment (by year of treatment) and stratifies this risk by anti-JCV antibody level (index value), as derived from an anti-JCV antibody assay that has been analytically validated in MS patients (the STRATIFY JCV assay).
Patients who have all three risk factors for developing PML (i.e. are anti-JCV antibody positive and have received more than 2 years of Tysabri therapy and have received prior immunosuppressant therapy) have a significantly higher risk of developing PML as determined during studies using a two step ELISA anti-JCV antibody assay, although the relative risk may vary using other assays.
In patients not previously treated with immunosuppressants, the level of anti-JCV antibodies (index value) can further stratify risk for developing PML. Index values equal to or below 0.9 are associated with a PML incidence of less than 1 per 1000 patients; PML risk increases substantially at index values above 1.5.
The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who have all three of these risk factors for PML or those patients who have no prior immunosuppressant use and have an index value of greater than 1.5 and more than two years of treatment with Tysabri.
Patients who are anti-JCV antibody negative are at a significantly lower risk of developing PML.
The risk of acquiring PML estimated from clinical trials is generally consistent with the risk estimated from postmarketing data. Data on the safety and efficacy of Tysabri at two years were generated from controlled, double blind studies. Postmarketing data are available from use up to six years, although data beyond 6 years are limited.

JCV granule cell neuronopathy.

JCV also causes granule cell neuronopathy (GCN) which has been reported in patients treated with Tysabri. Symptoms of JCV GCN are similar to symptoms of PML (i.e. cerebellar syndrome, although cerebellar atrophy may be a differential feature on MRI), and diagnosis and management of JCV GCN should follow guidance provided for PML (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).

PML, plasma exchange (PLEX) and IRIS (immune reconstitution inflammatory syndrome).

In Tysabri patients that develop PML, IRIS occurs in almost all cases after withdrawal or removal of Tysabri, e.g. by plasma exchange (PLEX). IRIS is thought to result from the restoration of immune function in patients with PML. IRIS presents as a worsening in neurological status that may be rapid, which can lead to serious neurological complications and may be fatal. Monitoring for development of IRIS, which has occurred within days to several weeks after plasma exchange in Tysabri treated patients with PML, and appropriate treatment of the associated inflammation during recovery from PML should be undertaken.
Based on a retrospective analysis of natalizumab-treated patients since its approval, no difference was observed on 2-year survival after PML diagnosis between patients who received PLEX and those who did not. Physicians should use medical judgement when considering the use of PLEX to treat PML.
The impact of plasma exchange on the restitution of lymphocyte migration and ultimately its clinical usefulness is unknown (see Section 5.2 Pharmacokinetic Properties).

Other opportunistic infections.

Other opportunistic infections have been reported with the use of Tysabri, primarily in patients with Crohn's disease who were immunocompromised or where significant comorbidity existed (see Section 4.8 Adverse Effects (Undesirable Effects), Infections). However increased risk of other opportunistic infections with use of Tysabri in patients without these comorbidities cannot currently be excluded.
Serious, life threatening and sometimes fatal reports of encephalitis and meningitis caused by herpes simplex or varicella zoster have been seen. The duration of treatment with Tysabri prior to onset ranged from a few months to several years. If herpes encephalitis or meningitis occurs, Tysabri should be discontinued and appropriate treatment for herpes encephalitis or meningitis should be administered.
Acute retinal necrosis (ARN) is a fulminant viral infection of the retina caused by the family of herpes viruses (e.g. varicella zoster). ARN has been observed in patients being administered Tysabri and can be potentially blinding (see Section 4.8 Adverse Effects (Undesirable Effects), Infections). Patients presenting with eye symptoms such as decreased visual acuity, redness and painful eye should be referred for retinal screening for ARN. Following clinical diagnosis of ARN and institution of antiviral therapy where appropriate, discontinuation of Tysabri should be considered in these patients.
Physicians should be aware of the possibility that other opportunistic infections may occur during Tysabri therapy and should include them in the differential diagnosis of infections that occur in Tysabri treated patients. If an opportunistic infection is suspected, dosing with Tysabri is to be suspended until such infections can be excluded through further evaluations.
If a patient receiving Tysabri develops an opportunistic infection, dosing of Tysabri must be permanently discontinued.

Hepatotoxicity.

Spontaneous suspect adverse drug reactions of liver injury, including severe liver injury, have been reported from the market. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose. Signs of liver injury have also been reported for the first time after multiple doses, including cases with rechallenge. In these patients recovery of liver function occurred following cessation of therapy.
If liver injury occurs during treatment with Tysabri the drug should be discontinued and investigation of cause undertaken. Tysabri should be initiated with caution in patients with a history of liver disease and liver function tests should be regularly monitored in these patients.

Stopping Tysabri therapy - prolonged pharmacodynamic effects.

If a decision is made to stop treatment with Tysabri, the physician needs to be aware that natalizumab remains in the blood and may have pharmacodynamic effects (e.g. increased lymphocyte counts) for approximately 12 weeks following the last dose. Starting other therapies during this interval may result in a concomitant exposure to Tysabri. For drugs such as interferon and glatiramer acetate, concomitant exposure of this duration was not associated with safety risks in clinical trials. No data are available in MS patients regarding concomitant exposure with immunosuppressant medication. Use of these medicines soon after the discontinuation of Tysabri may lead to an additive immunosuppressive effect. This should be carefully considered on a case by case basis, and a wash out period of Tysabri might be appropriate. Also see Section 4.4 Special Warnings and Precautions for Use, Progressive multifocal leukoencephalopathy.

Hypersensitivity.

Tysabri has been associated with hypersensitivity reactions, including anaphylactic/ anaphylactoid reactions, which occurred at an incidence of < 1%. These reactions usually occurred during administration or up to 1 hour after completion of administration, but there have been occasional postmarket reports of delays of up to 2 weeks in symptom onset. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypertension, hypotension, dyspnoea and chest pain. Generally, these reactions are associated with antibodies to Tysabri.
The risk for hypersensitivity was greatest with early infusions and in patients re-exposed to Tysabri following an initial short exposure (up to three infusions) and extended period (three months or more) without treatment. Neurologists should counsel patients on the importance of uninterrupted dosing, particularly in the early months of treatment. However, the risk of hypersensitivity reactions should be considered for every administration.
Patients should be observed during administration and for 1 hour after the completion of administration (also see Section 4.2 Dose and Method of Administration). Resources for the management of hypersensitivity reactions should be available.
If a hypersensitivity reaction occurs, discontinue administration of Tysabri and initiate appropriate therapy. Patients who have experienced a hypersensitivity reaction should not be retreated with Tysabri. The possibility of antibodies to Tysabri should be considered in patients who have hypersensitivity reactions (see Section 4.8 Adverse Effects (Undesirable Effects), Immunogenicity).

Immunogenicity.

Disease exacerbations or administration-related events may indicate the development of antibodies against natalizumab (see Section 4.8 Adverse Effects (Undesirable Effects)). If, after approximately 6 months of therapy, persistent antibodies are suspected, they may be detected and confirmed with a subsequent test 6 weeks after the first positive test. Antibodies detected early in the treatment course (e.g. within the first 6 months) may be transient and disappear with continued dosing. Given that efficacy may be reduced, or the incidence of hypersensitivity or administration-related reactions may be increased in a patient with persistent antibodies, physicians should consider the overall benefits and risks of continuing therapy with Tysabri and cessation of treatment may be appropriate. Patients who receive Tysabri for a short exposure followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure. Following a prolonged dose interruption (three months or more), consideration should be given to testing for the presence of persistent antibodies (detected on two occasions at least 6 weeks apart) prior to resuming treatment.

Use in hepatic impairment.

Tysabri has not been studied in patients with hepatic impairment in clinical trials.

Use in renal impairment.

Tysabri has not been studied in patients with renal impairment in clinical trials.

Use in the elderly.

Clinical studies of Tysabri did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients.

Paediatric and adolescent use.

Safety and effectiveness of Tysabri in paediatric and adolescent patients with multiple sclerosis below the age of 18 have not been established. Currently available data are described in Adverse Effects (Undesirable Effects), Paediatric and Pharmacodynamic Properties, Clinical trials.

Immunisations.

In a randomised, open label study of 60 patients with relapsing MS there was no significant difference in the humoral immune response to either a neoantigen (keyhole limpet haemocyanin) or a recall antigen (tetanus toxoid) between patients who were treated with Tysabri for 6 months compared to an untreated control group. Live vaccines have not been studied. No data are available on the secondary transmission of infection by live vaccines in patients receiving Tysabri.

Effects on laboratory tests.

Tysabri induces increases in circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. Elevations of neutrophils are not observed. Tysabri induces mild decreases in haemoglobin levels that are frequently transient. Haematological changes persist during Tysabri exposure but are reversible, returning to baseline levels usually within 16 weeks after the last dose, and are not associated with clinical symptoms.
In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, blood chemistry, including liver function tests, are recommended for patients with a history of liver disease or active liver disease, during treatment with Tysabri.

Extended interval dosing (EID).

Extended interval dosing of Tysabri (average dosing interval of approximately 6 weeks) has been used in the post-market setting. However, the efficacy of extended interval dosing has not been established and the associated benefit risk balance is currently unknown.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The safety and efficacy of Tysabri in combination with antineoplastic or immunosuppressive agents have not been established. Concurrent use of these agents with Tysabri may increase the risk of infections, including PML and other opportunistic infections (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects), Infections).
In phase 3 clinical trials in multiple sclerosis (studies 1 and 2), concomitant treatment of relapses with a short course of corticosteroids was associated with an increased rate of infection. However, the increase in infections was similar in Tysabri treated patients who received steroids compared with placebo treated patients who received steroids. Short courses of corticosteroids can be used in combination with Tysabri.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In guinea pigs, intravenous administration of natalizumab was associated with reduced female fertility at an estimated systemic exposure (serum AUC) of 18 times that in humans at the recommended clinical dose, but not at 3 times clinical exposure. Intravenous administration of natalizumab to male guinea pigs did not affect fertility at an estimated exposure 21 times clinical exposure (serum AUC).
(Category C)
Studies in animals have shown reproductive toxicity.
Natalizumab crossed the placenta in guinea pigs and monkeys, but there was no evidence of teratogenicity at respective maternal exposures up to 16 times and 100 times clinical exposure (based on AUC), including effects on early cardiac development (a process known to involve α4 integrins). Intravenous administration of natalizumab to pregnant monkeys during the period of organogenesis was associated with foetal changes (mild anaemia, thrombocytopaenia, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary haematopoiesis, thymic atrophy and decreased hepatic haematopoiesis), at estimated maternal exposures of 17 times or greater (based on AUC) the clinical exposure at the recommended dose. At the no-effect dose, the extent of maternal exposure was uncertain. Offspring born to monkeys treated intravenously with high doses of natalizumab (100 times clinical exposure based on AUC) showed thrombocytopaenia (reversed upon clearance of natalizumab) and enlarged spleen, but there was no evidence of anaemia.
Intravenous administration of natalizumab to guinea pigs during late gestation and lactation was associated with reduced pup viability, with maternal exposure (based on AUC) estimated at 18-fold clinical exposure. At the no-effect dose, maternal exposure was 3-fold clinical exposure.
There are no adequate and well controlled studies of Tysabri therapy in pregnant women. This drug should be used during pregnancy only if clearly needed. If a woman becomes pregnant while taking Tysabri, discontinuation of therapy should be considered.
Cases of thrombocytopenia in infants born to women exposed to Tysabri during pregnancy were reported in the post-marketing setting. Cases of increased white blood cell counts and transient mild to moderate anaemia, from published literature, were reported in infants born to women exposed to natalizumab in their third trimester. Therefore, monitoring for haematological abnormalities is recommended for neonates born to women exposed to Tysabri during pregnancy.
 Tysabri has been detected in human milk. Because of this, and because the potential for serious adverse reactions is unknown, a decision should be made whether to discontinue breastfeeding or Tysabri therapy.
Intravenous administration of natalizumab to guinea pigs during late gestation and lactation was associated with reduced pup viability, with estimated maternal exposure (AUC) 18-fold that in humans at the recommended clinical dose and 3-fold clinical exposure at the no effect dose.

4.7 Effects on Ability to Drive and Use Machines

The effect of Tysabri on the ability to drive or use machines has not been studied.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Intravenous infusion. In placebo controlled trials in 1617 MS patients treated with Tysabri for up to 2 years (placebo: 1135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with Tysabri (placebo: 4.8%). Over the 2 year duration of the studies, 43.5% of patients treated with Tysabri reported adverse drug reactions (an adverse event judged related to therapy by the investigating physician) (placebo: 39.6%).
Table 1 includes adverse events and selected laboratory abnormalities that occurred in study 1 (monotherapy study) at an incidence of at least 1% higher in Tysabri treated patients than was observed in placebo treated patients.
Adverse drug reactions reported with Tysabri with an incidence of 0.5% greater than reported with placebo and not already included in Table 1 are shown below. The reactions are reported as MedDRA preferred terms under the MedDRA primary system organ class. Frequencies were defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100).

Infections and infestations.

Very common: nasopharyngitis.

Immune system disorders.

Common: urticaria.

Nervous system disorders.

Very common: dizziness.

Gastrointestinal disorders.

Very common: nausea.
Common: vomiting.

General disorders and administration site conditions.

Common: pyrexia.
No trials were conducted directly comparing the adverse event profile of Tysabri plus Avonex to Tysabri alone. When comparing across trials, in general, adverse events appeared to be more common in those receiving Tysabri in combination with Avonex than those receiving Tysabri alone (99.2% vs. 95.1%, Tysabri plus Avonex vs Tysabri, respectively). Many of these differences appeared to be attributable to adverse events often associated with beta-interferon (headache, fatigue, depression, arthralgia, flu-like symptoms). Peripheral oedema and herpes viral infections were slightly more common in those receiving Tysabri in combination with Avonex than those receiving Tysabri alone. The overall incidence of serious adverse events and serious infections were similar in those receiving Tysabri in addition to Avonex as compared with Tysabri alone, although appendicitis was slightly more common in those receiving combination treatment (0.8% vs. 0.2%).
Subcutaneous administration. The safety profile observed for natalizumab administered subcutaneously in 162 patients was consistent with the known safety profile of natalizumab administered intravenously, with the exception of injection-site pain or reactions. During the two clinical trials with subcutaneous administration (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties), the overall frequency of injection-site pain or reactions was 7.4% (12/162) in subjects receiving natalizumab subcutaneously.

Description of selected adverse effects.

Infusion related reactions.

In 2 year controlled clinical trials in MS patients (studies 1 and 2), an infusion related event was defined as an adverse event occurring during the infusion or within 1 hour of the completion of the infusion. Approximately 24% of Tysabri treated MS patients experienced an infusion related reaction, compared to 18% of placebo treated patients. Infusion related reactions in Tysabri treated patients included headache, dizziness, fatigue, rigors and localised or multisymptomatic hypersensitivity reactions.

Hypersensitivity.

The majority of hypersensitivity reactions are infusion related. No delayed hypersensitivity reactions were seen in 2 year controlled clinical studies in MS patients receiving natalizumab intravenously (studies 1 and 2). In studies 1 and 2, hypersensitivity reactions occurred in up to 4% of patients. This includes acute urticaria, which was observed in approximately 2% of patients.
Anaphylactic/ anaphylactoid reactions occurred in < 1% of patients. All patients recovered with treatment and/or discontinuation of the infusion.
Patients who became persistently positive for antibodies to Tysabri were more likely to have an infusion related reaction than those who were antibody negative (see Section 4.8 Adverse Effects (Undesirable Effects), Immunogenicity).
No serious hypersensitivity reactions were observed in 162 patients with natalizumab for subcutaneous administration in 2 clinical trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).

Immunogenicity.

Patients in study 1 and study 2 were tested for antibodies to natalizumab every 12 weeks. Antibodies against natalizumab were detected in approximately 10% of multiple sclerosis patients receiving Tysabri in 2 year controlled clinical trials in MS patients. Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 6 weeks later) developed in approximately 6% of patients. Antibodies were detected on only one occasion in an additional 4% of patients. Approximately 90% of patients who became persistently antibody positive by this assay had developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralising in vitro.
Persistent antibodies to natalizumab were associated with a substantial decrease in the effectiveness of Tysabri and an increased incidence of hypersensitivity reactions. The risk of disability progression and the annualised relapse rate of persistently antibody positive Tysabri treated patients were similar to the rates in subjects who received placebo.
Infusion related reactions most often associated with persistent antibody positivity included urticaria, rigors, nausea, vomiting and flushing. Additional adverse events more common in persistently antibody positive patients included myalgia, hypertension, dyspnoea, anxiety and tachycardia.
If, after approximately 6 months of therapy, persistent antibodies are suspected, they may be detected and confirmed with a subsequent test 6 weeks after the first positive test. Given that efficacy may be reduced or the incidence of hypersensitivity or infusion related reactions may be increased in a patient with persistent antibodies, physicians should consider the overall benefits and risks of therapy with Tysabri and cessation of treatment may be appropriate.

Infections.

In 2 year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patient year in both Tysabri treated patients and placebo treated patients. The nature of the infections were generally similar in Tysabri treated and placebo treated patients. The infections were predominately upper respiratory tract infections, influenza and urinary tract infections. Most patients did not interrupt treatment with Tysabri during the infection and recovery occurred with appropriate treatment.
Cases of PML have been reported in clinical trials. In the postmarketing setting, additional cases of PML in patients treated with Tysabri monotherapy have been reported (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Progressive multifocal leukoencephalopathy).
The only opportunistic infection in multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course. In clinical studies for other indications, opportunistic infections (e.g. Pneumocystis carinii pneumonia, pulmonary Mycobacterium avium intracellulare, bronchopulmonary aspergillosis) were observed uncommonly in Tysabri treated patients; the majority of these patients were either receiving concurrent immunosuppressants or had major comorbidities.
In clinical trials, herpes infections occurred slightly more frequently in patients treated with Tysabri than in patients treated with placebo. In postmarketing experience, serious life threatening, and sometimes fatal cases of encephalitis and meningitis caused by herpes simplex or varicella zoster have been reported in multiple sclerosis patients receiving Tysabri (see Section 4.4 Special Warnings and Precautions for Use, Other opportunistic infections).
In postmarketing experience, acute retinal necrosis (ARN) has been observed at a higher incidence in patients receiving natalizumab. Some cases have occurred in patients with central nervous system herpes infections (e.g. herpes meningitis and encephalitis). Serious cases of ARN, affecting one or both eyes, led to blindness in some patients. The treatment reported in these cases included antiviral therapy and, in some cases, surgery.

Malignancies.

No differences in incidence rates or the nature of malignancies between Tysabri and placebo treated patients were observed over 2 years of treatment. However, observation over longer treatment periods is required before any effect of Tysabri on malignancies can be excluded.

Post-marketing experience.

Clinically significant liver injury has been reported in patients treated with Tysabri in the postmarketing setting (see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity).
PML has been reported in patients treated with Tysabri monotherapy in the postmarketing setting, including cases with onset in the absence of clinical symptoms. (See Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Progressive multifocal leukoencephalopathy). Some cases have been reported up to 6 months following discontinuation of Tysabri therapy. Cases of JCV granule cell neuronopathy (GCN) have also been reported during postmarketing use of Tysabri. Symptoms of JCV GCN are similar to PML.
In postmarketing experience, there have been reports of eosinophilia (eosinophil count > 1,500/mm3) without clinical findings. In cases where Tysabri therapy was discontinued the elevated eosinophil levels resolved. There have also been reports of uncommon frequency of thrombocytopenia and immune thrombocytopenic purpura (ITP).
Serious, rare cases of haemolytic anaemia have been reported in patients treated with Tysabri in postmarketing observational studies.

Paediatric.

Serious adverse events were evaluated in 621 MS paediatric patients from the meta-analysis study (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Within the limitations of these data, there were no new safety signals identified in this patient population. One case of herpes meningitis was reported in the meta-analysis. No cases of PML were identified in the meta-analysis, however, PML has been reported in natalizumab treated paediatric patients in the post-marketing setting. Safety and effectiveness of Tysabri in paediatric patients less than 18 years of age have not been established.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of Tysabri that can be safely administered has not been determined.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tysabri binds to the α4-subunit of α4β1 and α4β7-integrins expressed on the surface of all leucocytes except neutrophils, and inhibits the α4 mediated adhesion of leucocytes to their counter receptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium and mucosal addressin cell adhesion molecule-1 (MadCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leucocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-α4-integrin antibodies also block α4 mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1).
The specific mechanism(s) by which Tysabri exerts its effects in multiple sclerosis have not been fully defined. In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood brain barrier (BBB). Leucocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leucocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical relevance of these animal data is unknown.
Based on PK/α4β1 integrin binding relationships established in the updated population pharmacokinetic/pharmacodynamic model, the EC50 of natalizumab binding to α4β1 integrin is estimated to be 2.5 mg/L. The levels α4-integrin saturation appeared to be similar after either subcutaneous or intravenous administration of natalizumab 300 mg every 4 weeks.
Tysabri administration increases the number of circulating leucocytes (including lymphocytes, monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space. Tysabri does not affect the number of circulating neutrophils (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).

Clinical trials.

Intravenous administration.

Tysabri was evaluated in two randomised, double blind, placebo controlled trials in patients with relapsing remitting multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0. Patients with primary progressive, secondary progressive and progressive relapsing MS were excluded from these trials.
In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Magnetic resonance imaging evaluations for T1 weighted gadolinium (Gd) enhancing lesions and T2 hyperintense lesions were performed annually.
Study 1 enrolled patients who had not received any interferon beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Median age was 37, with a median disease duration of 5 years. Patients were randomised in a 2:1 ratio to receive Tysabri 300 mg intravenous infusion (n = 627) or placebo (n = 315) every 4 weeks for up to 28 months (30 infusions).
Study 2 enrolled patients who had experienced one or more relapses while on treatment with Avonex (interferon beta-1a) 30 microgram intramuscularly (IM) once weekly during the year prior to study entry. Median age was 39, with a median disease duration of 7 years. Patients were evenly randomised to receive Tysabri 300 mg (n = 589) or placebo (n = 582) every 4 weeks for up to 28 months (30 infusions). All patients continued to receive Avonex 30 microgram IM once weekly. In this study, Tysabri in combination with Avonex was compared with Avonex alone.
In both studies, there were two prespecified primary endpoints, annualised clinical relapse rate at one year and disease progression, measured by Extended Disability Severity Scale (EDSS), at two years. Sustained increase in disability was defined as an increase of at least 1 point on the EDSS from baseline EDSS ≥ 1.0 that was sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS = 0 that was sustained for 12 weeks. Results are shown in Tables 2 and 3. Median time on study drug was 120 weeks in each study.
Time to onset of sustained increase in disability was longer in patients treated with Tysabri than in patients treated with placebo in studies 1 (see Figure 3) and 2. The proportions of patients with increased disability and annualised relapse rate were also lower in patients treated with Tysabri than in patients treated with placebo in studies 1 and 2. Subgroup and sensitivity analyses showed results consistent with the primary analyses. The sensitivity analysis of increase in disability that was sustained for 24 weeks yielded a 54% reduction in the Tysabri group in study 1 (p < 0.001).
Changes in MRI findings often do not correlate with changes in the clinical status of patients (e.g. disability progression). The prognostic significance of the MRI findings in these studies has not been evaluated.
Study 101MS101 was an open label, randomised, crossover study in 43 patients with relapsing forms of multiple sclerosis comparing the pharmacokinetic properties of natalizumab produced by the initial manufacturing process and natalizumab manufactured using the high titre process. As a secondary endpoint, the tolerability and safety of both manufacturing processes were assessed. No notable differences were observed in the overall incidence for any safety measures in patients receiving either natalizumab preparation. The safety profile over this 36 week study was similar to that described in other natalizumab studies.
Study 101MS201 was a multicentre, open label, repeat dose study of 113 natalizumab naïve patients with relapsing forms of multiple sclerosis assessing the immunogenicity of 300 mg of natalizumab manufactured using the high titre process. Natalizumab was administered intravenously over 60 minutes every 4 weeks for 9 months (a total of 9 doses). A secondary objective was to evaluate safety. All subjects received at least one dose of natalizumab. Natalizumab manufactured using the high titre process was well tolerated with an adverse event profile similar to that observed in previous clinical studies. Persistent anti-natalizumab antibodies formed in a small number of subjects which is comparable to the rate observed with previous clinical studies.
A meta-analysis was conducted using data from 621 paediatric MS patients treated with Tysabri (median age 17 years, range was 7-18 years, 91% aged ≥ 14 years). Within the meta-analysis, a limited subset of patients with data available prior to treatment (158 of the 621 patients) in the post-marketing setting demonstrated a reduction in annualised relapse rate (ARR) from 1.466 (95% CI 1.337, 1.604) prior to treatment to 0.110 (95% CI 0.094, 0.128).

Subcutaneous administration.

The efficacy and safety of Tysabri for subcutaneous administration was explored in a randomised, blinded, parallel-group, Phase 2 study (REFINE, 101MS206) that explored the safety, tolerability, and efficacy of multiple regimens of natalizumab (300 mg intravenously every 4 weeks (n=54), 300 mg subcutaneously every 4 weeks (n=45), 300 mg intravenously every 12 weeks (n=52), 300 mg subcutaneously every 12 weeks (n=53), 150 mg intravenously every 12 weeks (n=47) and 150 mg subcutaneously every 12 weeks (n=38)) in adult subjects (n=290) with relapsing multiple sclerosis over a 60-week period.
The primary endpoint of this study was the cumulative number of combined unique active (CUA) MRI lesions (sum of new Gd+ lesions on brain MRI and new or newly enlarging T2 hyperintense lesions not associated with Gd+ on T1 weighted scans). The mean CUA for the 300 mg SC every 4 weeks arm was low (0.02) and comparable to the 300 mg IV every 4 weeks arm (0.23). The mean CUA in the every 12 weeks treatment arms was significantly higher than the every 4 weeks treatment arms and resulted in the early discontinuation of the every 12 week arms. Due to the descriptive nature of this exploratory study, no formal statistical efficacy comparisons were made. The study therefore has quite limited interpretation regarding comparative efficacy, on its own.

5.2 Pharmacokinetic Properties

Intravenous administration.

Following the repeat intravenous administration of a 300 mg dose of natalizumab to patients with multiple sclerosis (MS), the mean (± standard deviation) maximum observed serum concentration was 110 ± 52 microgram/mL. Mean average steady-state trough concentrations ranged from 23 microgram/mL to 29 microgram/mL. The observed time to steady state was approximately 24 weeks.
An updated population pharmacokinetic analysis was conducted consisting of 11 studies and data with serial PK sampling as measured by an industry standard assay. It included 1,286 subjects receiving doses ranging from 1 to 6 mg/kg and fixed doses of 150/300 mg. Population median estimate for linear clearance was 6.21 mL/h, (5.60-6.70 mL/h, 95% confidence interval), median steady-state volume of distribution was 5.58 L (5.27-5.92 L, 95% confidence interval) and the estimated median terminal half-life was 26.8 days.
The population analysis of 1,286 patients explored the effects of selected covariates including bodyweight, age, gender, presence of anti-natalizumab antibodies and formulation on natalizumab pharmacokinetics. Only body weight, the presence of anti-natalizumab antibodies and the formulation used in phase 2 studies were found to influence natalizumab disposition. Natalizumab clearance increased with bodyweight in a less than proportional manner, such that a +/-43% change in bodyweight resulted in a -38% to 36% change in clearance. Variation of clearance with body weight is not considered clinically relevant. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 2.54-fold, consistent with reduced serum natalizumab concentrations observed in persistently antibody-positive patients (see Section 4.8 Adverse Effects (Undesirable Effects), Immunogenicity). Clearance also increased by 2.17 fold for the phase 2 formulation compared to commercially used formulation.
Study 101MS101 was an open label, randomised, crossover study in 43 subjects with relapsing forms of multiple sclerosis comparing the pharmacokinetic properties of natalizumab produced by the initial manufacturing process and natalizumab manufactured using the high titre process. Nearly identical concentration/ time profiles were observed. Comparability of both manufacturing methods was well demonstrated.
The effect of plasma exchange on natalizumab clearance and pharmacodynamics was evaluated in a study of 12 MS patients. Estimates of the total drug removal after 3 plasma exchanges (over a 5-8 day interval) was approximately 70-80%. This compares to approximately 40% seen in earlier studies in which measurements occurred after drug discontinuation over a similar period of observation. The impact of plasma exchange on the restitution of lymphocyte migration and ultimately its clinical usefulness is unknown.
The pharmacokinetics of Tysabri in paediatric or adolescent MS patients younger than 18 years have not been established. Pharmacokinetics in patients over 65 years of age, or patients with renal or hepatic insufficiency have not been studied.

Subcutaneous administration.

The pharmacokinetics of natalizumab after subcutaneous administration was evaluated in 2 studies. The DELIVER study (101MS102) was a phase 1, randomised, open-label, dose-ranging study to evaluate the pharmacokinetics of subcutaneous and intramuscular natalizumab in subjects with MS (n=76). (See Section 5.1 Pharmacodynamic Properties, Clinical trials for a description of the REFINE 101MS206 study.) A delay in peak natalizumab plasma concentration (Cmax) of 5.8 days (range: 2 to 7.9 days) was observed after administration of natalizumab 300 mg subcutaneously. After day 14, the disposition of natalizumab was consistent with that of the intravenous administration. Multiple subcutaneous doses of 300 mg administered every 4 weeks resulted in Ctrough comparable to 300 mg administered intravenously every 4 weeks. Both intravenous and subcutaneous administration of natalizumab every 4 weeks resulted in comparable α4β1 integrin binding.
The bioavailability of natalizumab after subcutaneous administration was 82% as estimated using the updated population pharmacokinetic analysis. The absorption from the injection site to systemic circulation was characterized by first-order absorption, with a model estimated delay of 3 hours. No covariates were observed for absorption. Both intravenous and subcutaneous routes of administration shared the same pharmacokinetic disposition parameters (CL, Vss, and t1/2) and the same sets of covariates as described in the updated population pharmacokinetic analysis.
Less than 5% of subjects in DELIVER and REFINE tested positive for persistent anti-drug antibodies (ADA) within each formulation (intravenous or subcutaneous).

5.3 Preclinical Safety Data

Genotoxicity.

Natalizumab was negative in genotoxicity assays in vitro (mouse lymphoma forward mutation assay, chromosomal aberration in human lymphocytes).

Carcinogenicity.

Natalizumab showed no effects on in vitro assays of α4-integrin positive tumour line proliferation/cytotoxicity. Xenograft transplantation of two α4-integrin positive human tumour lines (leukaemia, melanoma) into immunodeficient mice demonstrated no increase in tumour growth rates or metastasis resulting from natalizumab treatment.

6 Pharmaceutical Particulars

6.1 List of Excipients

The concentrated solution for intravenous infusion and subcutaneous injection contain the same excipients:
Sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, polysorbate 80, water for injections.

6.2 Incompatibilities

Other medications should not be injected into infusion set side ports or mixed with Tysabri.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tysabri single use vials and prefilled syringes must be stored between 2°C to 8°C. Do not use after the expiration date on the carton and label. Do not shake or freeze. Protect from light (store in carton).
If not used immediately, diluted solution for infusion can be stored at 2°C to 8°C, protected from light. Tysabri solution for infusion must be administered within 72 hours of preparation.
The prefilled syringes can be kept in their original packaging for up to 24 hours at room temperature. The prefilled syringe should not be returned to refrigeration. Do not use external heat sources, such as hot water, to warm the prefilled syringe.

6.5 Nature and Contents of Container

Tysabri concentrated injection solution for infusion contains 300 mg/15 mL natalizumab in a sterile, single-use vial (Type I glass) with a stopper (chlorobutyl rubber) and a seal (aluminium) with a flip-off cap, free of preservatives (packs of 1 vial).
Tysabri injection solution for subcutaneous injection contains 150 mg/1 mL natalizumab in a sterile, single-use prefilled syringe (type I glass) with a stopper (halobutyl rubber coated with ethylene tetrafluoroethylene), stainless steel needle, a passive needle guard, plunger rod and finger flange (packs of 2 pre-filled syringes).*
Tysabri is for single use in one patient only.
* Not currently marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Schematic drawing of the major natalizumab structure.

CAS number.

189261-10-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes