TYSABRI- natalizumab injection

United States - English - NLM (National Library of Medicine)

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Active ingredient:
natalizumab (UNII: 3JB47N2Q2P) (natalizumab - UNII:3JB47N2Q2P)
Available from:
Biogen Inc.
INN (International Name):
natalizumab
Composition:
natalizumab 300 mg in 15 mL
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
TYSABRI is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases the risk of PML [see Warnings and Precautions (5.1) ]. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. TYSABRI is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. TYSABRI should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [see Warnings and Precautions (5.1) ]. - TYSABRI is contraindicated in patients who have or have had progressive mult
Product summary:
TYSABRI (natalizumab) injection, a sterile, preservative-free, colorless and clear to slightly opalescent solution for dilution prior to intravenous infusion, is supplied as one 300 mg/15 mL (20 mg/mL) single-dose vial per carton (NDC 64406-008-01). TYSABRI is available only through registered infusion centers participating in the TOUCH® Prescribing Program. To locate these infusion centers, contact Biogen at 1-800-456-2255. TYSABRI single-dose vials must be refrigerated between 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date stamped on the carton and vial label. DO NOT SHAKE OR FREEZE. Protect from light. Store diluted TYSABRI solution refrigerated at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration (2.3) ]
Authorization status:
Biologic Licensing Application
Authorization number:
64406-008-01

TYSABRI- natalizumab injection

Biogen Inc.

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This Medication Guide has been approved by the U.S. Food and Drug

Administration.

Revised 06/2020

MEDICATION GUIDE

TYSABRI® (tie-SA-bree)

(natalizumab)

injection, for intravenous use

Read this Medication Guide before you start receiving TYSABRI and before you receive each dose. There

may be new information. This Medication Guide does not take the place of talking to your doctor about your

medical condition or your treatment.

What is the most important information I should know about TYSABRI?

TYSABRI increases your chance (risk) of getting a rare brain infection that usually leads to death or

severe disability. This infection is called progressive multifocal leukoencephalopathy (PML). If PML

happens, it usually happens in people with weakened immune systems.

There is no known treatment, prevention, or cure for PML.

Your chance of getting PML may be higher if you are also being treated with other medicines

that can weaken your immune system, including other treatments for Multiple Sclerosis (MS)

and Crohn's disease (CD). You should not take certain medicines that weaken your immune

system at the same time you are taking TYSABRI. Even if you use TYSABRI alone to treat

your MS or CD, you can still get PML.

Your risk of getting PML is higher if you:

have been infected by the John Cunningham Virus (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 who are infected by JCV do

not know it or do not have any symptoms. This infection usually happens in

childhood. Before you start receiving TYSABRI or during your treatment, your doctor

may do a blood test to check if you have been infected by JCV.

have received TYSABRI for a long time, especially longer than 2 years

have received certain medicines that can weaken your immune system before you start

receiving TYSABRI

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

other risk factors for getting PML during TYSABRI treatment that we do not know about yet.

Your doctor should discuss the risks and benefits of TYSABRI treatment with you before you

decide to receive TYSABRI. See “What are the possible side effects of TYSABRI?”

While you receive TYSABRI, and for 6 months after you stop receiving TYSABRI, it is

important that you call your doctor right away if you have any new or worsening medical

problems that have lasted several days.

These may be new or sudden and include problems with:

thinking

balance

eyesight

weakness on 1 side of

strength

using your arms and legs

your body

Tell all your doctors that you are receiving TYSABRI.

Because of your risk of getting PML while you receive TYSABRI, TYSABRI is available only

through a restricted distribution program called the TOUCH®Prescribing Program. To receive

TYSABRI, you must talk to your doctor and understand the risks and benefits of TYSABRI and

agree to follow all of the instructions in the TOUCH® Prescribing Program.

TYSABRI is only:

prescribed by doctors who are enrolled in the TOUCH® Prescribing Program

given at an infusion center that is enrolled in the TOUCH® Prescribing Program

given to people who are enrolled in the TOUCH® Prescribing Program

Before you receive TYSABRI, your doctor will:

explain the TOUCH® Prescribing Program to you

have you sign the TOUCH® Prescriber and Patient Enrollment Form

What is TYSABRI?

TYSABRI is a prescription medicine used to treat adults with:

relapsing forms of Multiple Sclerosis (MS), to include clinically isolated syndrome, relapsing-

remitting disease and active secondary progressive disease. TYSABRI increases the risk of PML.

When starting and continuing treatment with TYSABRI, it is important that you discuss with your

doctor whether the expected benefit of TYSABRI is enough to outweigh this risk. See “What is the

most important information I should know about TYSABRI?”

moderate to severe Crohn's disease (CD). TYSABRI is used:

to reduce signs and symptoms of CD

in people who have not been helped enough by, or cannot use the usual CD medicines and

medicines called tumor necrosis factor (TNF) inhibitors.

It is not known if TYSABRI is safe and effective in children under 18 years of age.

Who should not receive TYSABRI?

Do not receive TYSABRI if you:

have PML

are allergic to natalizumab or any of the ingredients in TYSABRI. See the end of this Medication

Guide for a complete list of ingredients in TYSABRI.

Talk to your doctor before receiving TYSABRI if you have any of these conditions.

What should I tell my doctor before receiving each dose of TYSABRI?

Before you receive TYSABRI, tell your doctor if you:

have medical conditions that can weaken your immune system, including:

HIV infection or AIDS

leukemia or lymphoma

an organ transplant

other medical conditions that can weaken your immune system

have any new or worsening medical problems that have lasted several days. These may be new or

sudden and include problems with:

thinking

strength

eyesight

weakness on 1 side of your

balance

using your arms and legs

body

have had hives, itching or trouble breathing during or after receiving a dose of TYSABRI

have a fever or infection (including shingles or any unusually long lasting infection)

are pregnant or plan to become pregnant. It is not known if TYSABRI can harm your unborn baby.

are breastfeeding or plan to breastfeed. TYSABRI can pass into your breast milk. It is not known if

the TYSABRI that passes into your breast milk can harm your baby. Talk to your doctor about the

best way to feed your baby while you receive TYSABRI.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,

vitamins and herbal supplements. Especially tell your doctor if you take medicines that can weaken your

immune system. Ask your doctor if you are not sure.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new

medicine.

How should I receive TYSABRI?

TYSABRI is given 1 time every 4 weeks through a needle placed in your vein (IV infusion).

Before each TYSABRI dose you will be asked questions to make sure TYSABRI is still right for

you.

What are the possible side effects of TYSABRI?

TYSABRI may cause serious side effects, including:

See “What is the most important information I should know about TYSABRI?”

Herpes Infections. TYSABRI may increase your risk of getting an infection of the brain or the

covering of your brain and spinal cord (encephalitis or meningitis) caused by herpes viruses that may

lead to death. Call your doctor right away if you have sudden fever, severe headache, or if you feel

confused after receiving TYSABRI. Herpes infections of the eye, causing blindness in some patients,

have also occurred. Call your doctor right away if you have changes in vision, eye redness, or eye

pain.

Liver damage. Symptoms of liver damage can include:

yellowing of the skin and eyes

(jaundice)

unusual darkening of the urine

nausea

feeling tired or weak

vomiting

Call your doctor right away if you have symptoms of liver damage. Your doctor can do blood tests to check

for liver damage.

Allergic reactions, including serious allergic reactions. Symptoms of an allergic reaction can include:

hives

dizziness

nausea

itching

wheezing

flushing of skin

trouble breathing

chills

low blood pressure

chest pain

rash

Serious allergic reactions usually happen within 2 hours of the start of your infusion, but they can happen at

any time after you receive TYSABRI.

Tell your doctor right away if you have any symptom of an allergic reaction, even if it happens after you

leave the infusion center. You may need treatment if you are having an allergic reaction.

Infections. TYSABRI may increase your chance of getting an unusual or serious infection because

TYSABRI can weaken your immune system. You have a higher risk of getting infections if you also

take other medicines that can weaken your immune system.

Low platelet counts. TYSABRI may cause the number of platelets in your blood to be reduced. Call

your healthcare provider if you have any of the following symptoms:

easy bruising

heavier menstrual periods than are normal

bleeding from your gums or nose that is new or

takes longer than usual to stop

bleeding from a cut that is hard to stop

small scattered red spots on your skin that are

red, pink, or purple

The most common side effects of TYSABRI include:

headache

lung infection

vaginitis

stomach area

pain

feeling tired

depression

rash

urinary tract

infection

pain in your arm

and legs

nose and throat

infections

joint pain

diarrhea

nausea

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects of TYSABRI. Ask your doctor for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

General information about the safe and effective use of TYSABRI.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about TYSABRI. If you would like

more information, talk with your doctor. You can ask your pharmacist or doctor for information about

TYSABRI that is written for healthcare professionals.

For more information, go to www.TYSABRI.com or call 1-800-456-2255.

What are the ingredients in TYSABRI?

Active ingredient: natalizumab

Inactive Ingredients: sodium chloride, sodium phosphate, monobasic, monohydrate; sodium phosphate,

dibasic, heptahydrate; polysorbate 80, and water for injection

Manufactured by: Biogen Inc.; Cambridge, MA 02142 USA

Revised: 6/2020

Document Id: 7628d515-59db-47b7-8ba9-95dc94363af5

34391-3

Set id: c5fdde91-1989-4dd2-9129-4f3323ea2962

Version: 35

Effective Time: 20200630

Biogen Inc.

TYSABRI- natalizumab injection

Biogen Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TYSABRI safely and effectively. See full

prescribing information for TYSABRI.

TYSABRI (natalizumab) injection, for intravenous use

Initial U.S. Approval: 2004

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

See full prescribing information for complete boxed warning

TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic

viral infection of the brain that usually leads to death or severe disability (5.1)

Risk factors for the development of PML include the presence of anti-JCV antibodies, duration of

therapy, and prior use of immunosuppressants. These factors should be considered in the context of

expected benefit when initiating and continuing treatment with TYSABRI (5.1)

Monitor patients, and withhold TYSABRI immediately at the first sign or symptom suggestive of PML

(4, 5.1)

Because of the risk of PML, TYSABRI is available only through a restricted distribution program

called the TOUCH Prescribing Program (5.1, 5.2)

RECENT MAJOR CHANGES

Boxed Warning

06/2020

Indications and Usage (1.1)

08/2019

Warnings and Precautions (5.1, 5.8)

06/2020

INDICATIONS AND USAGE

TYSABRI is an integrin receptor antagonist indicated for treatment of:

Multiple Sclerosis (MS)

TYSABRI is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically

isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases

the risk of PML [See Warnings and Precautions (5.1)]. When initiating and continuing treatment with TYSABRI, physicians

should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. (1.1)

Crohn's Disease (CD)

TYSABRI is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to

severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable

to tolerate, conventional CD therapies and inhibitors of TNF-α. (1.2)

Important Limitations:

In CD, TYSABRI should not be used in combination with immunosuppressants or inhibitors of TNF-α. (1.2)

DOSAGE AND ADMINISTRATION

300 mg infused intravenously over one hour, every four weeks. Do not give as an intravenous push or bolus (2.1, 2.2)

TYSABRI solution must be administered within 8 hours of preparation (2.3)

Observe patients during the infusion and for one hour after the infusion is complete (2.4)

In CD, discontinue in patients that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in

patients that cannot discontinue chronic concomitant steroids within six months of starting therapy (2.2)

DOSAGE FORMS AND STRENGTHS

Injection: 300 mg/15 mL (20 mg/mL) solution in a single-dose vial for dilution prior to infusion (3)

CONTRAINDICATIONS

Patients who have or have had PML (4)

Patients who have had a hypersensitivity reaction to TYSABRI (4, 5.3)

WARNINGS AND PRECAUTIONS

Herpes infections: Life-threatening and fatal cases have occurred with herpes encephalitis and meningitis infections.

®

Blindness has occurred in patients developing acute retinal necrosis. Discontinue TYSABRI if these infections occur

and treat appropriately (5.3)

Hepatotoxicity: Significant liver injury, including liver failure requiring transplant, has occurred. Discontinue TYSABRI

in patients with evidence of liver injury (5.4)

Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have occurred. Permanently

discontinue TYSABRI if such a reaction occurs (5.5)

Immunosuppression/Infections: TYSABRI may increase the risk for certain infections. Monitor patients for

development of infections due to increased risk with use of TYSABRI (5.6)

Thrombocytopenia: TYSABRI may cause thrombocytopenia. Monitor patients for bleeding abnormalities. Discontinue

TYSABRI in patients with thrombocytopenia (5.8)

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥ 10%):

MS - headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis,

depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash (6.1)

CD - headache, upper respiratory tract infections, nausea, and fatigue (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm. (8.1)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 6/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

1 INDICATIONS AND USAGE

1.1 Multiple Sclerosis (MS)

1.2 Crohn's Disease (CD)

2 DOSAGE AND ADMINISTRATION

2.1 Multiple Sclerosis (MS)

2.2 Crohn's Disease (CD)

2.3 Dilution Instructions

2.4 Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Progressive Multifocal Leukoencephalopathy

5.2 TYSABRI TOUCH Prescribing Program

5.3 Herpes Infections

5.4 Hepatotoxicity

5.5 Hypersensitivity/Antibody Formation

5.6 Immunosuppression/Infections

5.7 Laboratory Test Abnormalities

5.8 Thrombocytopenia

5.9 Immunizations

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Multiple Sclerosis

14.2 Crohn's Disease

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an

opportunistic viral infection of the brain that usually leads to death or severe disability. Risk

factors for the development of PML include the presence of anti-JCV antibodies, duration

of therapy, and prior use of immunosuppressants. These factors should be considered in

the context of expected benefit when initiating and continuing treatment with TYSABRI [see

Warnings and Precautions (5.1)].

Healthcare professionals should monitor patients on TYSABRI for any new sign or

symptom that may be suggestive of PML. TYSABRI dosing should be withheld

immediately at the first sign or symptom suggestive of PML. For diagnosis, an

evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI)

scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are

recommended [see Contraindications (4), Warnings and Precautions (5.1)].

Because of the risk of PML, TYSABRI is available only through a restricted program

under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH

Prescribing Program [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

1.1 Multiple Sclerosis (MS)

TYSABRI is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to

include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive

disease, in adults. TYSABRI increases the risk of PML [see Warnings and Precautions (5.1)]. When

initiating and continuing treatment with TYSABRI, physicians should consider whether the expected

benefit of TYSABRI is sufficient to offset this risk.

1.2 Crohn's Disease (CD)

Sections or subsections omitted from the full prescribing information are not listed.

®

TYSABRI is indicated for inducing and maintaining clinical response and remission in adult patients

with moderately to severely active Crohn's disease with evidence of inflammation who have had an

inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α.

TYSABRI should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine,

azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [see Warnings and Precautions

(5.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Multiple Sclerosis (MS)

Only prescribers registered in the MS TOUCH Prescribing Program may prescribe TYSABRI for

multiple sclerosis [see Warnings and Precautions (5.2)]. The recommended dose of TYSABRI for

multiple sclerosis is 300 mg intravenous infusion over one hour every four weeks.

2.2 Crohn's Disease (CD)

Only prescribers registered in the CD TOUCH Prescribing Program may prescribe TYSABRI for

Crohn's disease [see Warnings and Precautions (5.2)].

The recommended dose of TYSABRI for Crohn's disease is 300 mg intravenous infusion over one

hour every four weeks. TYSABRI should not be used with concomitant immunosuppressants (e.g., 6-

mercaptopurine, azathioprine, cyclosporine, or methotrexate) or concomitant inhibitors of TNF-α.

Aminosalicylates may be continued during treatment with TYSABRI.

If the patient with Crohn's disease has not experienced therapeutic benefit by 12 weeks of induction

therapy, discontinue TYSABRI. For patients with Crohn's disease who start TYSABRI while on chronic

oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of TYSABRI has

occurred; if the patient with Crohn's disease cannot be tapered off of oral corticosteroids within six

months of starting TYSABRI, discontinue TYSABRI. Other than the initial six-month taper, prescribers

should consider discontinuing TYSABRI for patients who require additional steroid use that exceeds

three months in a calendar year to control their Crohn's disease.

2.3 Dilution Instructions

1. Use aseptic technique when preparing TYSABRI solution for intravenous infusion. Each vial is

intended for single use only. Discard any unused portion.

2. TYSABRI is a colorless, clear to slightly opalescent solution. Inspect the TYSABRI vial for

particulate material and discoloration prior to dilution and administration. If visible particulates are

observed and/or the liquid in the vial is discolored, the vial must not be used.

3. To prepare the diluted solution, withdraw 15 mL of TYSABRI from the vial using a sterile needle

and syringe. Inject TYSABRI into 100 mL of 0.9% Sodium Chloride Injection, USP. No other

intravenous diluents may be used to prepare the TYSABRI diluted solution.

4. Gently invert the TYSABRI diluted solution to mix completely. Do not shake. Inspect the solution

visually for particulate material prior to administration.

5. The final dosage diluted solution has a concentration of 2.6 mg/mL.

6. Following dilution, infuse TYSABRI solution immediately, or refrigerate the diluted solution at

2°C to 8°C, and use within 8 hours. If stored at 2°C to 8°C, allow the diluted solution to warm to

room temperature prior to infusion. DO NOT FREEZE.

2.4 Administration Instructions

Infuse TYSABRI 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over approximately one

hour (infusion rate approximately 5 mg per minute). Do not administer TYSABRI as an intravenous

push or bolus injection. After the infusion is complete, flush with 0.9% Sodium Chloride Injection,

USP.

Observe patients during the infusion and for one 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 Warnings and Precautions (5.5)].

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.

3 DOSAGE FORMS AND STRENGTHS

Injection: 300 mg /15 mL (20 mg/mL) colorless and clear to slightly opalescent solution in a single-dose

vial for dilution prior to infusion.

4 CONTRAINDICATIONS

TYSABRI is contraindicated in patients who have or have had progressive multifocal

leukoencephalopathy (PML) [see Warnings and Precautions (5.1)].

TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI.

Observed reactions range from urticaria to anaphylaxis [see Warnings and Precautions (5.5)].

5 WARNINGS AND PRECAUTIONS

5.1 Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused

by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that

usually leads to death or severe disability, has occurred in patients who have received TYSABRI.

Three factors that are known to increase the risk of PML in TYSABRI-treated patients have been

identified:

The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk

for developing PML.

Longer treatment duration, especially beyond 2 years.

Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate,

cyclophosphamide, mycophenolate mofetil).

These factors should be considered in the context of expected benefit when initiating and continuing

treatment with TYSABRI.

Table 1: Estimated United States Incidence of PML Stratified by Risk Factor

Notes: The risk estimates are based on postmarketing data in the United States from approximately 100,000

TYSABRI exposed patients.

The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically and

clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific

antibodies with an analytical false negative rate of 3%.

Anti-JCV

Antibody

Negative

TYSABRI

Exposure

Anti-JCV Antibody Positive

No Prior Immunosuppressant Use

Prior Immunosuppressant Use

1/10,000

1-24 months

<1/1,000

1/1,000

25-48 months

2/1,000

6/1,000

49-72 months

4/1,000

7/1,000

73-96 months

2/1,000

6/1,000

Retrospective analyses of postmarketing data from various sources, including observational studies and

spontaneous reports obtained worldwide, suggest that the risk of developing PML may be associated

with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often

described as an anti-JCV antibody index value).

Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have

systemic medical conditions resulting in significantly compromised immune system function should not

be treated with TYSABRI. Infection by the JC virus is required for the development of PML. Anti-JCV

antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that

antibodies to the JC virus have not been detected. Patients who are anti-JCV antibody negative have a

lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at

risk for the development of PML due to the potential for a new JCV infection or a false negative test

result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody

negative to positive and remaining positive in subsequent testing) is 3 to 8 percent annually. In addition,

some patients' serostatus may change intermittently. Therefore, patients with a negative anti-JCV

antibody test result should be retested periodically. For purposes of risk assessment, a patient with a

positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the

results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status

should be determined using an analytically and clinically validated immunoassay. After plasma exchange

(PLEX), wait at least two weeks to test for anti-JCV antibodies to avoid false negative test results

caused by the removal of serum antibodies. After infusion of intravenous immunoglobulin (IVIg), wait at

least 6 months (5 half-lives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test

results.

Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom

suggestive of PML. Symptoms associated with PML are diverse, progress over days to weeks, and

include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision,

and changes in thinking, memory, and orientation leading to confusion and personality changes. The

progression of deficits usually leads to death or severe disability over weeks or months. Withhold

TYSABRI dosing immediately and perform an appropriate diagnostic evaluation at the first sign or

symptom suggestive of PML.

MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on

MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs

or symptoms specific to PML, have been reported. Many of these patients subsequently became

symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may

be useful, and any suspicious findings should lead to further investigation to allow for an early

diagnosis of PML, if present. Consider monitoring patients at high risk for PML more frequently.

Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation in

patients with PML who were initially asymptomatic compared to patients with PML who had

characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are

due to early detection and discontinuation of TYSABRI or due to differences in disease in these

patients.

There are no known interventions that can reliably prevent PML or that can adequately treat PML if it

occurs. PML has been reported following discontinuation of TYSABRI in patients who did not have

findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for

any new signs or symptoms that may be suggestive of PML for at least six months following

discontinuation of TYSABRI.

Because of the risk of PML, TYSABRI is available only under a restricted distribution program, the

TOUCH Prescribing Program.

In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with TYSABRI.

This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML.

In Crohn's disease patients, a baseline brain MRI may also be helpful to distinguish pre-existent lesions

from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while

on TYSABRI therapy are uncommon.

For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when

indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial evaluations for

PML are negative but clinical suspicion for PML remains, continue to withhold TYSABRI dosing, and

repeat the evaluations.

There are no known interventions that can adequately treat PML if it occurs. Three sessions of PLEX

over 5 to 8 days were shown to accelerate TYSABRI clearance in a study of 12 patients with MS who

did not have PML, although in the majority of patients, alpha-4 integrin receptor binding remained high.

Adverse events which may occur during PLEX include clearance of other medications and volume

shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not

been prospectively studied in TYSABRI-treated patients with PML, it has been used in such patients in

the postmarketing setting to remove TYSABRI more quickly from the circulation. There is no evidence

that PLEX has any benefit in the treatment of opportunistic infections such as PML.

JC virus infection of granule cell neurons in the cerebellum (i.e., JC virus granule cell neuronopathy

[JCV GCN]) has been reported in patients treated with TYSABRI. JCV GCN can occur with or without

concomitant PML. JCV GCN can cause cerebellar dysfunction (e.g., ataxia, incoordination, apraxia,

visual disorders), and neuroimaging can show cerebellar atrophy. For diagnosis of JCV GCN, an

evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal

fluid analysis for JC viral DNA, is recommended. JCV GCN should be managed similarly to PML.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI

treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS

occurred after PLEX was used to eliminate circulating TYSABRI. It presents as a clinical decline in the

patient's condition after TYSABRI removal (and in some cases after apparent clinical improvement) that

may be rapid, can lead to serious neurological complications or death, and is often associated with

characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing

treatment with TYSABRI for reasons unrelated to PML. In TYSABRI treated patients with PML, IRIS

has been reported within days to several weeks after PLEX. Monitoring for development of IRIS and

appropriate treatment of the associated inflammation should be undertaken.

5.2 TYSABRI TOUCH Prescribing Program

TYSABRI is available only through a restricted program under a REMS called the TOUCH

Prescribing Program because of the risk of PML [see Warnings and Precautions (5.1)].

For prescribers and patients, the TOUCH Prescribing Program has two components: MS TOUCH

(for patients with multiple sclerosis) and CD TOUCH (for patients with Crohn's disease).

Selected requirements of the TOUCH Prescribing Program include the following:

Prescribers must be certified and comply with the following:

®

Review the TOUCH Prescribing Program prescriber educational materials, including the

full prescribing information.

Educate patients on the benefits and risks of treatment with TYSABRI, ensure that patients

receive the Medication Guide, and encourage them to ask questions.

Review, complete, and sign the Patient-Prescriber Enrollment Form.

Evaluate patients three months after the first infusion, six months after the first infusion, every

six months thereafter, and for at least six months after discontinuing TYSABRI.

Determine every six months whether patients should continue on treatment and, if so, authorize

treatment for another six months.

Submit to Biogen the “TYSABRI Patient Status Report and Reauthorization Questionnaire” six

months after initiating treatment and every six months thereafter.

Complete an “Initial Discontinuation Questionnaire” when TYSABRI is discontinued, and a “6-

Month Discontinuation Questionnaire” following discontinuation of TYSABRI.

Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide,

understand the risks associated with TYSABRI, and complete and sign the Patient-Prescriber

Enrollment Form.

Pharmacies and infusion centers must be specially certified to dispense or infuse TYSABRI.

5.3 Herpes Infections

Herpes Encephalitis and Meningitis

TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and

varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the

postmarketing setting in multiple sclerosis patients receiving TYSABRI. Laboratory confirmation in

those cases was based on positive PCR for viral DNA in the cerebrospinal fluid. The duration of

treatment with TYSABRI prior to onset ranged from a few months to several years. Monitor patients

receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or

meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes

encephalitis/meningitis should be administered.

Acute Retinal Necrosis

Acute retinal necrosis (ARN) is a fulminant viral infection of the retina caused by the family of herpes

viruses (e.g., varicella zoster, herpes simplex virus). A higher risk of ARN has been observed in

patients being administered TYSABRI. Patients presenting with eye symptoms, including decreased

visual acuity, redness, or eye pain, should be referred for retinal screening for ARN. Some ARN cases

occurred in patients with central nervous system (CNS) herpes infections (e.g., herpes meningitis or

encephalitis). Serious cases of ARN led to blindness of one or both eyes in some patients. Following

clinical diagnosis of ARN, consider discontinuation of TYSABRI. The treatment reported in ARN

cases included anti-viral therapy and, in some cases, surgery.

5.4 Hepatotoxicity

Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in

patients treated with TYSABRI in the postmarketing setting. 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. In some

patients, liver injury recurred upon rechallenge, providing evidence that TYSABRI caused the injury.

The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is

generally recognized as an important predictor of severe liver injury that may lead to death or the need

for a liver transplant in some patients.

TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury

(e.g., laboratory evidence).

5.5 Hypersensitivity/Antibody Formation

Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic

reactions (e.g., anaphylaxis), which occurred at an incidence of <1%. These reactions usually occur

within two hours of the start of the infusion. Symptoms associated with these reactions can include

urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain.

Generally, these reactions are associated with antibodies to TYSABRI.

If a hypersensitivity reaction occurs, discontinue administration of TYSABRI, and initiate appropriate

therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI.

Hypersensitivity reactions were more frequent in patients with antibodies to TYSABRI compared to

patients who did not develop antibodies to TYSABRI in both MS and CD studies. Therefore, the

Report cases of PML, hospitalizations due to opportunistic infections, and deaths to Biogen at

1-800-456-2255 as soon as possible.

possibility of antibodies to TYSABRI should be considered in patients who have hypersensitivity

reactions [see Adverse Reactions (6.2)].

Antibody testing: If the presence of persistent antibodies is suspected, antibody testing should be

performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies

detected early in the treatment course (e.g., within the first six months) may be transient and may

disappear with continued dosing. It is recommended that testing be repeated three months after an initial

positive result to confirm that antibodies are persistent. Prescribers should consider the overall benefits

and risks of TYSABRI in a patient with persistent antibodies.

Patients who receive TYSABRI for a short exposure (1 to 2 infusions) followed by an extended period

without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity

reactions on re-exposure, compared to patients who received regularly scheduled treatment. Given that

patients with persistent antibodies to TYSABRI experience reduced efficacy, and that hypersensitivity

reactions are more common in such patients, consideration should be given to testing for the presence

of antibodies in patients who wish to recommence therapy following a dose interruption. Following a

period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of

antibody development with re-treatment that is similar to TYSABRI naïve patients [see Adverse Reactions

(6.2)].

5.6 Immunosuppression/Infections

The immune system effects of TYSABRI may increase the risk for infections. In Study MS1 [see Clinical

Studies (14.1)], certain types of infections, including pneumonias and urinary tract infections (including

serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections,

occurred more often in TYSABRI-treated patients than in placebo-treated patients [see Warnings and

Precautions (5.1), Adverse Reactions (6.1)]. One opportunistic infection, a cryptosporidial gastroenteritis

with a prolonged course, was observed in a patient who received TYSABRI in Study MS1.

In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short

courses of corticosteroids. However, the increase in infections in TYSABRI-treated patients who

received steroids was similar to the increase in placebo-treated patients who received steroids.

In a long-term safety study of patients treated with TYSABRI for multiple sclerosis, opportunistic

infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and

meningitis, and Candida pneumonia) have been observed in <1% of TYSABRI-treated patients.

In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia, pulmonary

mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have

been observed in <1% of TYSABRI-treated patients; some of these patients were receiving concurrent

immunosuppressants [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

In Studies CD1 and CD2, an increase in infections was seen in patients concurrently receiving

corticosteroids. However, the increase in infections was similar in placebo-treated and TYSABRI-

treated patients who received steroids. Concurrent use of antineoplastic, immunosuppressant, or

immunomodulating agents may further increase the risk of infections, including PML and other

opportunistic infections, over the risk observed with use of TYSABRI alone [see Warnings and

Precautions (5.1), Adverse Reactions (6.1)]. The safety and efficacy of TYSABRI in combination with

antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients

receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical

conditions resulting in significantly compromised immune system function should not ordinarily be

treated with TYSABRI. The risk of PML is also increased in patients who have been treated with an

immunosuppressant prior to receiving TYSABRI [see Warnings and Precautions (5.1)].

For patients with Crohn's disease who start TYSABRI while on chronic corticosteroids, commence

steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot discontinue

systemic corticosteroids within six months, discontinue TYSABRI.

5.7 Laboratory Test Abnormalities

In clinical trials, TYSABRI was observed to induce increases in circulating lymphocytes, monocytes,

eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during TYSABRI

exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose.

Elevations of neutrophils were not observed. TYSABRI induces mild decreases in hemoglobin levels

(mean decrease of 0.6 g/dL) that are frequently transient.

5.8 Thrombocytopenia

Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported

with the use of TYSABRI in the postmarketing setting. Symptoms of thrombocytopenia may include easy

bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia

may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYSABRI should

be discontinued.

5.9 Immunizations

No data are available on the effects of vaccination in patients receiving TYSABRI. No data are

available on the secondary transmission of infection by live vaccines in patients receiving TYSABRI.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Progressive Multifocal Leukoencephalopathy (PML) [see Warnings and Precautions (5.1)]

Herpes Infections [see Warnings and Precautions (5.3)]

Hepatotoxicity [see Warnings and Precautions (5.4)]

Hypersensitivity/Antibody Formation [see Warnings and Precautions (5.5 )]

Immunosuppression/Infections [see Warnings and Precautions (5.6 )]

Thrombocytopenia [see Warnings and Precautions (5.8 )]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

The most common adverse reactions (incidence ≥ 10%) were headache and fatigue in both the multiple

sclerosis (MS) and Crohn's disease (CD) studies. Other common adverse reactions (incidence ≥ 10%) in

the MS population were arthralgia, urinary tract infection, lower respiratory tract infection,

gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash.

Other common adverse reactions (incidence ≥ 10%) in the CD population were upper respiratory tract

infections and nausea.

The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of

TYSABRI) in the MS studies were urticaria (1%) and other hypersensitivity reactions (1%), and in the

CD studies (Studies CD1 and CD2) were the exacerbation of Crohn's disease (4.2%) and acute

hypersensitivity reactions (1.5%) [see Warnings and Precautions (5.5)].

A total of 1617 multiple sclerosis patients in controlled studies received TYSABRI, with a median

duration of exposure of 28 months. A total of 1563 patients received TYSABRI in all CD studies for a

median exposure of 5 months; of these patients, 33% (n=518) received at least one year of treatment and

19% (n=297) received at least two years of treatment.

Multiple Sclerosis Clinical Studies

The most common serious adverse reactions in Study MS1 [see Clinical Studies (14.1)] with TYSABRI

were infections (3.2% versus 2.6% in placebo, including urinary tract infection [0.8% versus 0.3%] and

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